Heterocyclic inhibitors of erk1 and erk2 and their use in the treatment of cancer

ABSTRACT

The present application provides novel heterocyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful for inhibiting ERK1/2. By administering to a patient in need a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, Z, J, M, and R1 to R8 are defined herein, these compounds are effective in treating conditions associated with dysregulation of the RAS/RAF/MEK/ERK pathway. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/790,082, filed Feb. 13, 2020, which is a continuation of U.S.application Ser. No. 15/183,504, filed Jun. 15, 2016, now U.S. Pat. No.10,751,332, issued Aug. 25, 2020, which claims priority from U.S.Provisional Application No. 62/175,756, filed Jun. 15, 2015, thedisclosures of which are hereby incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic compounds useful asinhibitors of ERK1 and ERK2. The present invention further relates tocompositions containing such compounds, and methods of use thereof.

BACKGROUND OF THE INVENTION

ERK1 and ERK2 (collectively “ERK1/2”) are relatedprotein-serine/threonine kinases that participate in, amongst others,the Ras-Raf-MEK-ERK signal transduction pathway, which is sometimesdenoted as the mitogen-activated protein kinase (MAPK) pathway. Thispathway is thought to play a central role in regulating a number offundamental cellular processes including one or more of cellproliferation, survival, adhesion, cycle progression, migration,differentiation, metabolism, and transcription. The activation of theMAPK pathway has been reported in numerous tumor types including lung,colon, pancreatic, renal, and ovarian cancers. Accordingly, substancesthat could reduce activation could be of interest for possibletreatments.

ERK1/2 appear to be activated by MEK through phosphorylation of both athreonine and a tyrosine residue, namely at Tyr204/187 and Thr202/185.Once activated, ERK1/2 catalyze the phosphorylation of serine/threonineresidues of more than 100 substrates and activate both cytosolic andnuclear proteins that are linked to cell growth, proliferation,survival, angiogenesis and differentiation, all hallmarks of the cancerphenotype. Thus it may be beneficial to target ERK to develop and useERK1/2 inhibitors as a way to inhibit tumor growth.

Furthermore, an ERK inhibitor may have utility in combination with otherMAPK inhibitors. Recently, researchers reported that dual inhibition ofMEK and ERK by small molecule inhibitors was synergistic and acted toovercome acquired resistance to MEK inhibitors. See Hatzivassiliou etal., ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition,Mol. Cancer Ther. 2012, 11, 1143-1154.

Small molecular ERK inhibitors have been reported in the literatureincluding U.S. Pat. Nos. 6,743,941, 8,546,404, and Ren et al., Discoveryof Highly Potent, Selective and Efficacious Small Molecule Inhibitors ofERK1/2, J. Med. Chem., 2015, 58(4), 1976-1991. A small number of ERKinhibitors (e.g., BVD-523 and GDC-0994) are in early clinicaldevelopment. However, no ERK inhibitor has been reported to advance intolate stage clinical trials. Therefore, there is a continuing need forthe development of improved and efficacious ERK1/2 inhibitors for thetreatment of cancer.

SUMMARY OF THE INVENTION

The present invention addresses a compound of formula (I):

and a pharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof, wherein:

R¹ is unsubstituted or substituted C₆₋₁₂aryl or unsubstituted orsubstituted 5- to 10-membered heteroaryl;

J is a linker group selected from —C(R²)(R⁸)(CH₂)_(n)—;

R² and R⁸ are each independently H, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, or—C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl), wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, or heteroaryl is unsubstituted orsubstituted;

or R², R⁸, and the C atom that both R² and R⁸ are attached join togetherto form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclylring, wherein the cycloalkyl or heterocyclyl ring is unsubstituted orsubstituted;

n is 0 to 6;

R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens;

M is a bond or NH;

X and Y are each independently CH, C—R⁷, or N;

Z is CH or N,

R⁵ is H, halogen, C₁₋₆alkyl, or —O—C₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens;

R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens;

R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-5 halogens; and

R⁴ is unsubstituted or substituted C₁₋₆alkyl, unsubstituted orsubstituted C₃₋₁₀cycloalkyl, unsubstituted or substitutedC₄₋₁₀cycloalkenyl, unsubstituted or substituted 4- to 10-memberedheterocyclyl, unsubstituted or substituted phenyl, unsubstituted orsubstituted 5- to 10-membered heteroaryl, unsubstituted or substituted—C₁₋₆alkyl-(4- to 6-membered heterocycly), unsubstituted or substituted—C₁₋₆alkyl-(5- to 6-membered heteroaryl), or unsubstituted orsubstituted —C₁₋₆alkyl-phenyl.

The present invention further addresses a compound of formula (I), and apharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof, wherein:

R¹ is phenyl or 5- to 10-membered heteroaryl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, CN,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-N—(C₁₋₆alkyl)₂,—C₁₋₆alkyl-NH—C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₆alkyl, NH₂, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl;

J is —C(R²)(R⁸)(CH₂)_(n)

R² and R⁸ are each independently H, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, or—C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl), wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, NH₂,hydroxyC₁₋₆alkyl, or amino C₁₋₆alkyl;

or R², R⁸, and the C atom that both R² and R⁸ are attached join togetherto form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclylring, wherein the cycloalkyl or heterocyclyl is unsubstituted orsubstituted with 1-3 substituents selected from hydroxyl, halogen, orC₁₋₆alkyl;

n is 0 to 6;

R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens;

M is a bond or NH;

X and Y are each independently CH, C—R⁷, or N;

R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-5 halogens;

Z is CH or N;

R⁵ is H, halogen, C₁₋₆alkyl, or OC₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens;

R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens; and

R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, —C₁₋₆alkyl-phenyl,—C₁₋₆alkyl-(5- to 6-membered heteroaryl), —C₁₋₆alkyl-(4- to 6-memberedheterocyclyl), 5- to 10-membered heteroaryl, 4- to 10-memberedheterocyclyl, or phenyl, wherein the alkyl, cycloalkyl, cycloalkenyl,phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with1-3 substituents selected from halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and theheterocyclyl or heteroaryl is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or 4- to6-membered heterocyclyl.

The present invention further addresses a compound of formula (I), and apharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof, wherein:

R¹ is phenyl or thienyl which can be unsubstituted or substituted with1-3 substituents selected from halogen, C₁₋₆alkyl, or hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, or CN, wherein C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 halogens;

J is —CH(R²)—;

R² is H, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl);

R³ is H;

M is a bond;

X is CH;

Y is CH or N;

Z is N,

R⁵ is H, halogen, or C₁₋₆alkyl;

R⁶ is H; and

R⁴ is hydroxyC₁₋₆alkyl,

-   -   which can be unsubstituted or substituted with 1-3 substituents        selected from halogen or C₁₋₆alkoxy.

The present invention further addresses a compound selected from:

-   (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;-   N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methyl-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)-amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;    and-   N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof.

The present invention further addresses a pharmaceutically acceptablesalt of the compound of claim 1, which is selected from:

-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide    benzenesulfonic acid salt;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methyl-pyrimidin-4-yl)-1H-imidazole-4-carboxamide    benzenesulfonic acid salt; and-   (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide    benzenesulfonic acid salt.

The present invention further relates to compositions containing suchcompounds, and methods of use thereof in treating a condition treatableby inhibiting ERK1/2.

In one embodiment, the condition is a cancer of prostate, head, neck,eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone,lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries,vagina, testicles, skin, thyroid, blood, lymph nodes, kidney, liver,intestines, pancreas, brain, central nervous system, adrenal gland, skinor a leukemia or lymphoma.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel inhibitors of ERK1 and ERK2 offormula (I)

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof, wherein:

R¹ is phenyl or 5- to 10-membered heteroaryl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, CN,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-N—(C₁₋₆alkyl)₂,—C₁₋₆alkyl-NH—C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₆alkyl, NH₂, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl;

J is a linker group selected from —C(R²)(R⁸)(CH₂)_(n)—;

R² and R are each independently H, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, or—C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl), wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, NH₂,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl;

or R², R⁸, and the C atom that both R² and R⁸ are attached join togetherto form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclylring, wherein the cycloalkyl or heterocyclyl ring is unsubstituted orsubstituted with 1-3 substituents selected from hydroxyl, halogen, orC₁₋₆alkyl;

n is 0 to 6;

R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens;

M is a bond or NH;

X and Y are each independently CH, C—R⁷, or N;

Z is CH or N,

R⁵ is H, halogen, C₁₋₆alkyl, or OC₁₋₆alkyl, wherein C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens;

R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens;

R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-5 halogens; and

R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, —C₁₋₆alkyl-phenyl,—C₁₋₆alkyl-(5- to 6-membered heteroaryl), C₁₋₆alkyl-(4- to 6-memberedheterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl,phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with1-3 substituents selected from halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and theheterocyclyl or heteroaryl is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or 4- to6-membered heterocyclyl.

In one aspect, the present invention provides novel inhibitors of ERK1and ERK2 of formula (II)

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof, wherein:

R¹ is phenyl or 5- to 10-membered heteroaryl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, CN,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-N—(C₁₋₆alkyl)₂,—C₁₋₆alkyl-NH—C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₆alkyl, NH₂, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl;

n is 0 to 6;

R² is C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N(C₁₋₆alkyl)₂, or—C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl), wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, NH₂,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl; and

R⁸ is H or C₁₋₆alkyl;

alternatively, R², R⁸, and the C atom that both R² and R⁸ are attachedjoin together to form a 3- to 10-membered cycloalkyl or 4- to10-membered heterocyclyl ring, wherein the cycloalkyl or heterocyclyl isunsubstituted or substituted with 1-3 substituents selected fromhydroxyl, halogen, or C₁₋₆alkyl;

R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens;

M is a bond or NH;

X and Y are each independently CH, C—R⁷, or N;

Z is CH or N,

R⁵ is H, halogen, C₁₋₆alkyl, or O—C₁₋₆alkyl, wherein C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens;

R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens;

R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-5 halogens; and

R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, —C₁₋₆alkyl-phenyl,—C₁₋₆alkyl-(5 to 6-membered heteroaryl), —C₁₋₆alkyl-(4 to 6-memberedheterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl,phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with1-3 substituents selected from halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and theheterocyclyl or heteroaryl is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or 4- to6-membered heterocyclyl.

In one embodiment, a compound of formula (II) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, CN,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-3 substituents selected fromhalogen;

n is 0 to 1;

R² is C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N(C₁₋₆alkyl)₂, or—C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl), wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, NH₂,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl; and

R⁸ is H or C₁₋₆alkyl;

alternatively, R², R⁸, and the C atom that both R² and R⁸ are attachedjoin together to form a 3- to 6-membered cycloalkyl or 4- to 6-memberedheterocyclyl ring, wherein the cycloalkyl or heterocyclyl isunsubstituted or substituted with 1-3 substituents selected fromhydroxyl, halogen, or C₁₋₆alkyl;

R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-3 halogens;

M is a bond or NH;

X and Y are each independently CH, C—R⁷, or N;

Z is CH or N,

R⁵ is H, halogen, C₁₋₆alkyl, or O—C₁₋₆alkyl, wherein C₁₋₆alkyl isunsubstituted or substituted with 1-3 halogens;

R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-3 halogens;

R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 halogens; and

R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, —C₁₋₆alkyl-phenyl,—C₁₋₆alkyl-(5 to 6-membered heteroaryl), —C₁₋₆alkyl-(4 to 6-memberedheterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl,phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with1-3 substituents selected from halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and theheterocyclyl or heteroaryl is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or 4- to6-membered heterocyclyl.

In one embodiment, R¹ is unsubstituted or substituted C₆₋₁₂aryl orunsubstituted or substituted 5- to 10-membered heteroaryl. In oneembodiment, R¹ is phenyl or 5- to 6-membered heteroaryl containing 1-2ring heteroatoms selected from O, N or S, wherein the phenyl orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₆alkyl, NH₂, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl. In oneembodiment, R¹ is phenyl, pyridyl, thienyl, or thiazolyl, which isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl, wherein theC₁₋₆alkyl is unsubstituted or substituted with 1-3 substituents selectedfrom halogen. In one embodiment, R¹ is phenyl, pyridyl, thienyl, orthiazolyl, which is unsubstituted or substituted with 1-3 substituentsselected from F, Cl, C₁₋₃alkyl, CN, hydroxyC₁₋₃alkyl, or aminoC₁₋₃alkyl,wherein the C₁₋₃alkyl is unsubstituted or substituted with 1-3substituents selected from F. In one embodiment, R¹ is phenyl, pyridyl,thienyl, or thiazolyl, which is unsubstituted or substituted with 1-3substituents selected from F, Cl, CH₃, —C(CH₃)₃, CF₃, —CH₂OH, —CH₂CH₂OH,CH₂NH₂, CN, or —C(CH₃)₂OH. In one embodiment, R¹ is phenyl, which isunsubstituted or substituted with 1-3 substituents selected from F, Cl,CH₃, —C(CH₃)₃, CF₃, —CH₂OH, —CH₂CH₂OH, CH₂NH₂, CN, or —C(CH₃)₂OH.

In one embodiment, n is 0 to 6. In one embodiment, n is 0 to 2. In oneembodiment, n is 0 to 1. In one embodiment, n is 0.

In one embodiment, R² is C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N(C₁₋₆alkyl)₂, or—C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl), wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, NH₂,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl; and R⁸ is H or C₁₋₆alkyl. In oneembodiment, R² is C₁₋₃alkyl, hydroxyC₁₋₃alkyl, aminoC₁₋₃alkyl,—C₁₋₃alkyl-O—C₁₋₃alkyl, —C₁₋₃alkyl-NH—C₁₋₃alkyl,—C₁₋₃alkyl-N—(C₁₋₃alkyl)₂, —C₁₋₃alkyl-NH—C₁₋₃alkyl-OH,—C₁₋₃alkyl-NH—C₁₋₃alkyl-C₃₋₆cycloalkyl,—C₁₋₃alkyl-NH—C₁₋₃alkyl-NH—C₁₋₃alkyl, —C₁₋₃alkyl-NH—C(O)—C₁₋₃alkyl,—C₁₋₃alkyl-O—C(O)—C₁₋₃alkyl, —C₁₋₃alkyl-NH—C₀₋₃alkyl-(4- to 6-memberedheterocyclyl), —C(O)—NH₂, —C(O)—NH—C₁₋₃alkyl, —C(O)—N(C₁₋₃alkyl)₂, or—C₁₋₃alkyl-NH—C₀₋₃alkyl-(5- to 6-membered heteroaryl), wherein theC₁₋₃alkyl, cycloalkyl, heterocyclyl, or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₃alkyl, NH₂,hydroxyC₁₋₃alkyl, or aminoC₁₋₃alkyl; and R⁸ is H or C₁₋₃alkyl. In oneembodiment, R² is C₁₋₃alkyl, hydroxyC₁₋₃alkyl, aminoC₁₋₃alkyl,—C₁₋₃alkyl-NH—C₁₋₃alkyl, —C₁₋₃alkyl-NH—C₁₋₃alkyl-OH,—C₁₋₃alkyl-NH—C₀₋₃alkyl-(4- to 6-membered heterocyclyl), or—C₁₋₃alkyl-NH—C₀₋₃alkyl-(5- to 6-membered heteroaryl); and R⁸ is H. Inone embodiment, R² is CH₃, —CH₂OH, —CH₂NH₂, —CH₂OCH₃, —CH₂N(CH₃)₂,—CH₂NH(CH₃), —CH₂NHCH₂CH₂OH, —CH₂NHC(O)CH₃, —CH₂OC(O)CH(NH₂)CH₂CH(CH₃)₂,—C(O)NH₂, —CH₂NH—(tetrahydro-2H-pyran), or —CH₂NHCH₂-(pyrrole); and R⁸is H. In one embodiment, R² is CH₃, —CH₂OH, —CH₂NH₂, —CH₂NH(CH₃),—CH₂NHCH₂CH₂OH, —CH₂NH-(tetrahydro-2H-pyran), or —CH₂NHCH₂-(pyrrole);and R⁸ is H. In one embodiment, R² is —CH₂OH or —CH₂NH₂; and R⁸ is H.

In another embodiment, R², R⁸, and the C atom that both R² and Rareattached join together to form a 3- to 6-membered cycloalkyl or 4- to6-membered heterocyclyl ring, wherein the cycloalkyl or heterocyclyl isunsubstituted or substituted with 1-3 substituents selected fromhydroxyl, halogen, or C₁₋₆alkyl. In one embodiment, R², R⁸, and the Catom that both R² and Rare attached join together to form a 3- to6-membered cycloalkyl, which is unsubstituted or substituted with 1-3substituents selected from hydroxyl. In one embodiment, R², R⁸, and theC atom that both R² and Rare attached join together to form cyclobutyl,which is unsubstituted or substituted with hydroxyl.

In one embodiment, R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens. In one embodiment, R³ isH or C₁₋₃alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 halogens. In one embodiment, R³ is H or CH₃.

In one embodiment, M is a bond or NH. In one embodiment, M is a bond.

In one embodiment, X and Y are each independently CH, C—R⁷, or N. In oneembodiment, X is CH, C—CH₃ or N. In one embodiment, X is CH. In oneembodiment, Y is CH, C—CH₃ or N. In one embodiment, Y is N.

In one embodiment, R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens. In one embodiment, R⁷ isC₁₋₆alkyl. In one embodiment, R⁷ is CH₃.

In one embodiment, Z is CH or N. In one embodiment, Z is N.

In one embodiment, R is H, halogen, C₁₋₆alkyl, or O—C₁₋₆alkyl, whereinC₁₋₆alkyl is unsubstituted or substituted with 1-5 halogens. In oneembodiment, R⁵ is H, Cl, F, C₁₋₃alkyl, or —O—C₁₋₃alkyl, whereinC₁₋₃alkyl is unsubstituted or substituted with 1-3 halogens. In oneembodiment, R⁵ is H, Cl, F, CH₃, or —OCH₃.

In one embodiment, R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens. In one embodiment, R⁶ isH or CH₃. In one embodiment, R⁶ is H.

In one embodiment, R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,—C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-(5 to 6-membered heteroaryl),—C₁₋₆alkyl-(4 to 6-membered heterocyclyl), 4- to 10-memberedheterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein thealkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, CN, —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂,—O—C₁₋₆alkyl-NH₂, —O—C₁₋₆alkyl-NH—(C₁₋₆alkyl),—O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to 6-membered heterocyclyl, —C(O)-(4- to6-membered heterocyclyl), —O-phenyl, —O—C₁₋₆alkyl-(4- to 6-memberedheterocyclyl), C₁₋₆alkyl, C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, orhydroxyC₁₋₆alkyl, and the heterocyclyl or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, or 4- to 6-membered heterocyclyl.

In one embodiment, R⁴ is

wherein each L is independently selected from halogen, CN, C₂₋₆alknyl,C₁₋₆alkoxy, —C(O)NHC₁₋₆alkyl, —C(O)NH(C₁₋₆alkyl)₂,—O—C₁₋₆alkyl-NHC₁₋₆alkyl, or —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, and x is 0, 1,2, or 3.

In one embodiment, R⁴ is C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-3 substituents selected from hydroxyl, orC₁₋₆alkoxyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is C₃₋₁₀cycloalkyl or C₄₋₁₀cycloalkenyl, which isunsubstituted or substituted with 1-3 substituents selected fromhydroxyl, halogen, or hydroxyC₁₋₆alkyl. In one embodiment, R⁴ isC₃₋₆cycloalkyl or C₄₋₆cycloalkenyl, which is unsubstituted orsubstituted with 1-3 substituents selected from hydroxyl, F, Cl, orhydroxyC₁₋₃alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is 4- to 10-membered monocyclic or bicyclicheterocyclyl containing 1-2 ring heteroatoms or hetero groups selectedfrom O, N, S, S(═O), S(═O)₂, or C(═O), which is unsubstituted orsubstituted with 1-2 substituents selected from C₁₋₆alkyl. In oneembodiment, R⁴ is 4- to 6-membered monocyclic heterocyclyl containing1-2 ring heteroatoms or hetero groups selected from O, N or S(═O)₂,which is unsubstituted or substituted with 1-2 substituents selectedfrom C₁₋₃alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is phenyl, which is unsubstituted or substitutedwith 1-3 substituents selected from halogen, CN, C₂₋₆alknyl, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and the heterocyclyl orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or 4- to 6-memberedheterocyclyl. In one embodiment, R⁴ is

wherein each L is independently selected from halogen, CN, C₂₋₆alknyl,C₁₋₆alkoxy, C(O)NHC₁₋₆alkyl, or C(O)NH(C₁₋₆alkyl)₂, and n is 0, 1, 2, or3. In one embodiment, each L is independently selected from F, Cl, CN,C₁₋₃alkoxy, —C(O)N(CH₃)₂, and x is 0, 1, 2, or 3.

In one embodiment, R⁴ is 5- to 10-membered monocyclic or bicyclicheteroaryl containing 1-2 ring heteroatoms or hetero groups selectedfrom N, O, C(═O), or S, which is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl or C₄₋₆cycloalkenyl. Inone embodiment, R⁴ is 5- or 6-membered monocyclic heteroaryl containing1-2 ring heteroatoms selected from N or O, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen or CH₃. In oneembodiment, R⁴ is

In one embodiment, R⁴ is —C₁₋₆alkyl-(5- to 6-membered heteroaryl), whichis unsubstituted or substituted with 1-3 substituents selected fromhalogen or C₁₋₆alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is —C₁₋₆alkyl-phenyl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen or C₁₋₆alkyl. Inone embodiment, R⁴ is —CH₂-phenyl, which is unsubstituted or substitutedwith CH₃. In one embodiment, R⁴ is

In one embodiment, R⁴ is-C₁₋₆alkyl-(4- to 6-membered heterocyclyl),which is unsubstituted or substituted with 1-3 substituents selectedfrom halogen or C₁₋₆alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, a compound of formula (II) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, pyridyl, thienyl, orthiazolyl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, CN,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-3 substituents selected fromhalogen;

n is 0;

R² is C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-membered heterocyclyl), —C(O)—NH₂,—C₁₋₆alkyl-NH—C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C(O)—NH—C₁₋₆alkyl,—C(O)—N(C₁₋₆alkyl)₂, or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-memberedheteroaryl), wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, NH₂, hydroxyC₁₋₆alkyl, oraminoC₁₋₆alkyl; and

R⁸ is H;

R³ is H;

M is a bond;

X is CH;

Y is CH or N;

Z is N;

R⁵ is H, halogen, or C₁₋₆alkyl;

R⁶ is H; and

R⁴ is

which can be unsubstituted or substituted with 1-3 substituents selectedfrom halogen or C₁₋₆alkoxy.

In one embodiment, a compound of formula (II) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, or thienyl, which is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, oraminoC₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 substituents selected from halogen;

n is 0;

R² is C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-membered heterocyclyl), —C(O)—NH₂,—C₁₋₆alkyl-NH—C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C(O)—NH—C₁₋₆alkyl,—C(O)—N(C₁₋₆alkyl)₂, or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-memberedheteroaryl), wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, NH₂, hydroxyC₁₋₆alkyl, oraminoC₁₋₆alkyl; and

R⁸ is H;

R³ is H;

M is a bond;

X is CH;

Y is CH or N;

Z is N;

R⁵ is H, halogen, or C₁₋₆alkyl;

R⁶ is H; and

R⁴ is

which can be unsubstituted or substituted with 1-3 substituents selectedfrom halogen or C₁₋₆alkoxy.

In one embodiment, a compound of formula (II) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, which is unsubstituted or substituted with 1-3substituents selected from F or Cl;

n is 0;

R² is CH₂OH, CH₂NH₂, —CH₂NH(CH₃), —CH₂NHCH₂CH₂OH, —C(O)NH₂,—CH₂NH-(tetrahydro-2H-pyran), or —CH₂NH—CH₂-(1H-pyrrole); and

R⁸ is H;

R³ is H;

M is a bond;

X is CH;

Y is N;

Z is N;

R is CH₃;

R⁶ is H; and

R⁴ is

In one aspect, the present invention provides novel inhibitors of ERK1and ERK2 of formula (III)

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof, wherein:

R¹ is phenyl or 5- to 10-membered heteroaryl, wherein the phenyl orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4 to 6-memberedheterocyclyl), —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5 to 6-membered heteroaryl),—C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, or —C(O)—N(C₁₋₆alkyl)₂, wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl is unsubstitutedor substituted with 1-3 substituents selected from halogens, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl;

n is 0 to 6;

R³ is H or C₁₋₆alkyl, wherein C₁₋₆alkyl is unsubstituted or substitutedwith 1-5 halogens;

M is a bond or NH;

X and Y are each independently CH, C—R⁷, or N;

Z is CH or N,

R⁵ is H, halogen, C₁₋₆alkyl, or O—C₁₋₆alkyl, wherein C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens;

R⁶ is H or C₁₋₆alkyl, wherein C₁₋₆alkyl is unsubstituted or substitutedwith 1-5 halogens;

R⁷ is C₁₋₆alkyl, wherein C₁₋₆alkyl is unsubstituted or substituted with1-5 halogens; and

R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, —C₁₋₆alkyl-phenyl,—C₁₋₆alkyl-(5 to 6-membered heteroaryl), —C₁₋₆alkyl-(4- to 6-memberedheterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl,phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with1-3 substituents selected from halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4 to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and theheterocyclyl or heteroaryl is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, C(O)—C₁₋₆alkyl, or 4- to6-membered heterocyclyl.

In one embodiment, a compound of formula (III) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, pyridyl, thienyl, orthiazolyl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, CN,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-3 substituents selected fromhalogen;

n is 1 to 2;

R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-3 halogens;

M is a bond or NH;

X and Y are each independently CH, C—R⁷, or N;

Z is CH or N,

R⁵ is H, halogen, C₁₋₆alkyl, or O—C₁₋₆alkyl, wherein C₁₋₆alkyl isunsubstituted or substituted with 1-3 halogens;

R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted orsubstituted with 1-3 halogens;

R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 halogens; and

R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, —C₁₋₆alkyl-phenyl,—C₁₋₆alkyl-(5 to 6-membered heteroaryl), —C₁₋₆alkyl-(4 to 6-memberedheterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl,phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with1-3 substituents selected from halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and theheterocyclyl or heteroaryl is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or 4- to6-membered heterocyclyl.

In one embodiment, R¹ is unsubstituted or substituted C₆₋₁₂aryl orunsubstituted or substituted 5- to 10-membered heteroaryl. In oneembodiment, R¹ is phenyl or 5- to 6-membered heteroaryl containing 1-2ring heteroatoms selected from O, N or S, wherein the phenyl orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, or —C(O)—N(C₁₋₆alkyl)₂, wherein theC₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl is unsubstitutedor substituted with 1-3 substituents selected from halogen, C₁₋₆alkyl,NH₂, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl. In one embodiment, R¹ isphenyl, pyridyl, thienyl, orthiazolyl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl, CN,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-3 substituents selected fromhalogen. In one embodiment, R¹ is phenyl, pyridyl, thienyl, orthiazolyl, which is unsubstituted or substituted with 1-3 substituentsselected from F, Cl, C₁₋₃alkyl, CN, hydroxyC₁₋₃alkyl, or aminoC₁₋₃alkyl,wherein the C₁₋₃alkyl is unsubstituted or substituted with 1-3substituents selected from F. In one embodiment, R¹ is phenyl, pyridyl,thienyl, or thiazolyl, which is unsubstituted or substituted with 1-3substituents selected from F, Cl, CH₃, —C(CH₃)₃, CF₃, —CH₂OH, —CH₂CH₂OH,CH₂NH₂, CN, or —C(CH₃)₂OH. In one embodiment, R¹ is phenyl, which isunsubstituted or substituted with 1-3 substituents selected from F, Cl,CH₃, —C(CH₃)₃, CF₃, —CH₂OH, —CH₂CH₂OH, CH₂NH₂, CN, or —C(CH₃)₂OH.

In one embodiment, n is 0 to 6. In one embodiment, n is 1 to 2. In oneembodiment, n is 1.

In one embodiment, R³ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens. In one embodiment, R³ isH or C₁₋₃alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 halogens. In one embodiment, R³ is H or CH₃.

In one embodiment, M is a bond or NH. In one embodiment, M is a bond.

In one embodiment, X and Y are each independently CH, C—R⁷, or N. In oneembodiment, X is CH, C—CH₃ or N. In one embodiment, X is CH. In oneembodiment, Y is CH, C—CH₃ or N. In one embodiment, Y is N.

In one embodiment, R⁷ is C₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens. In one embodiment, R⁷ isC₁₋₆alkyl. In one embodiment, R⁷ is CH₃.

In one embodiment, Z is CH or N. In one embodiment, Z is N.

In one embodiment, R is H, halogen, C₁₋₆alkyl, or O—C₁₋₆alkyl, whereinC₁₋₆alkyl is unsubstituted or substituted with 1-5 halogens. In oneembodiment, R⁵ is H, Cl, F, C₁₋₃alkyl, or —O—C₁₋₃alkyl, whereinC₁₋₃alkyl is unsubstituted or substituted with 1-3 halogens. In oneembodiment, R⁵ is H, Cl, F, CH₃, or —OCH₃.

In one embodiment, R⁶ is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl isunsubstituted or substituted with 1-5 halogens. In one embodiment, R⁶ isH or CH₃. In one embodiment, R⁶ is H.

In one embodiment, R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,—C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-(5 to 6-membered heteroaryl),—C₁₋₆alkyl-(4 to 6-membered heterocyclyl), 4- to 10-memberedheterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein thealkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, CN, —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂,—O—C₁₋₆alkyl-NH₂, —O—C₁₋₆alkyl-NH—(C₁₋₆alkyl),—O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to 6-membered heterocyclyl, —C(O)-(4- to6-membered heterocyclyl), —O-phenyl, —O—C₁₋₆alkyl-(4- to 6-memberedheterocyclyl), C₁₋₆alkyl, C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, orhydroxyC₁₋₆alkyl, and the heterocyclyl or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, or 4- to 6-membered heterocyclyl.

In one embodiment R⁴ is

wherein each L is independently selected from halogen, CN, C₂₋₆alknyl,C₁₋₆alkoxy, —C(O)NHC₁₋₆alkyl, —C(O)NH(C₁₋₆alkyl)₂,—O—C₁₋₆alkyl-NHC₁₋₆alkyl, or —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, and x is 0, 1,2, or 3.

In one embodiment, R⁴ is C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-3 substituents selected from hydroxyl, orC₁₋₆alkoxyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is C₃₋₁₀cycloalkyl or C₄₋₁₀cycloalkenyl, which isunsubstituted or substituted with 1-3 substituents selected fromhydroxyl, halogen, or hydroxyC₁₋₆alkyl. In one embodiment, R⁴ isC₃₋₆cycloalkyl or C₄₋₆cycloalkenyl, which is unsubstituted orsubstituted with 1-3 substituents selected from hydroxyl, F, Cl, orhydroxyC₁₋₃alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is 4- to 10-membered heterocyclyl containing 1-2ring heteroatoms or hetero groups selected from O, N, S, S(═O), S(═O)₂,or C(═O), which is unsubstituted or substituted with 1-2 substituentsselected from C₁₋₆alkyl. In one embodiment, R⁴ is 4- to 6-memberedmonocyclic heterocyclyl containing 1-2 ring heteroatoms or hetero groupsselected from O, N or S(O)₂, which is unsubstituted or substituted with1-2 substituents selected from C₁₋₃alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is phenyl, which is unsubstituted or substitutedwith 1-3 substituents selected from halogen, C₂₋₆alknyl, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, and the heterocyclyl orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or 4- to 6-memberedheterocyclyl. In one embodiment R⁴ is

wherein each L is independently selected from halogen, CN, C₂₋₆alknyl,C₁₋₆alkoxy, C(O)NHC₁₋₆alkyl, or C(O)NH(C₁₋₆alkyl)₂, and n is 0, 1, 2, or3. In one embodiment, each L is independently selected from F, Cl, CN,C₁₋₃alkoxy, —C(O)N(CH₃)₂, and x is 0, 1, 2, or 3.

In one embodiment, R⁴ is 5- to 10-membered monocyclic or bicyclicheteroaryl containing 1-2 ring heteroatoms or hetero groups selectedfrom O, N, S, S(═O), S(═O)₂, or C(═O), which is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl orC₄₋₆cycloalkenyl. In one embodiment, R⁴ is 5- or 6-membered monocyclicheteroaryl containing 1-2 ring heteroatoms selected from N or O, whichis unsubstituted or substituted with 1-3 substituents selected fromhalogen or CH₃. In one embodiment, R⁴ is

In one embodiment, R⁴ is —C₁₋₆alkyl-(5- to 6-membered heteroaryl), whichis unsubstituted or substituted with 1-3 substituents selected fromhalogen or C₁₋₆alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is —C₁₋₆alkyl-phenyl, which is unsubstituted orsubstituted with 1-3 substituents selected from halogen or C₁₋₆alkyl. Inone embodiment, R⁴ is —CH₂-phenyl, which is unsubstituted or substitutedwith CH₃. In one embodiment, R⁴ is

In one embodiment, R⁴ is-C₁₋₆alkyl-(4- to 6-membered heterocyclyl),which is unsubstituted or substituted with 1-3 substituents selectedfrom halogen or C₁₋₆alkyl. In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, a compound of formula (III) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, or thienyl, which is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, oraminoC₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 substituents selected from halogen;

n is 1;

R³ is H;

M is a bond;

X is CH;

Y is N;

Z is N,

R⁵ is H, halogen, or C₁₋₆alkyl;

R⁶ is H; and

R⁴ is

which can be unsubstituted or substituted with 1-3 substituents selectedfrom halogen or C₁₋₆alkoxy.

In one embodiment, a compound of formula (III) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, which is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, oraminoC₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substitutedwith 1-3 substituents selected from halogen;

n is 1;

R³ is H;

M is a bond;

X is CH;

Y is N;

Z is N,

R⁵ is CH₃;

R⁶ is H; and

R⁴ is

which can be unsubstituted or substituted with 1-3 substituents selectedfrom halogen or C₁₋₆alkoxy.

In one embodiment, a compound of formula (III) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, which is unsubstituted or substituted with 1-3substituents selected from halogen, CH₂OH, or CH₂NH₂;

n is 1;

R³ is H;

M is a bond;

X is CH;

Y is N;

Z is N,

R⁵ is CH₃;

R⁶ is H; and

R⁴ is

which can be unsubstituted or substituted with 1-3 substituents selectedfrom halogen or C₁₋₆alkoxy.

In one embodiment, a compound of formula (III) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, which is substituted with 1-3 substituents selected fromF, Cl, CH₂OH, or CH₂NH₂, and at least one ortho position is substituted;

n is 1;

R³ is H;

M is a bond;

X is CH;

Y is N;

Z is N,

R⁵ is CH₃;

R⁶ is H; and

In one embodiment, a compound of formula (III) or a pharmaceuticallyacceptable salt, solvate, hydrate, or stereoisomer, wherein:

R¹ is phenyl, which is substituted with 1-3 substituents selected fromF, Cl, CH₂OH, or CH₂NH₂, and at least one ortho position is substitutedwith CH₂OH or CH₂NH₂;

n is 1;

R³ is H;

M is a bond;

X is CH;

Y is N;

Z is N,

R⁵ is CH₃;

R⁶ is H; and

R⁴ is

In one embodiment, the compound is one selected from:

-   (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;-   N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)-amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)-amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;    and-   N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,    or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or    stereoisomer thereof.

The compounds of formulae (I-III) are limited to those that arechemically feasible and stable. Therefore, a combination of substituentsor variables in the compounds described above is permissible only ifsuch a compound results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least for a week.

The compounds of formulae (I-III) and each of the species thereof, aloneor in combination, also are salts, prodrugs, solvates, hydrates, racemicforms, enantiomers, diastereomers, metabolites and mixtures thereof, tothe extent practicable, unless otherwise stated or inconsistent from thecontext.

Representative “pharmaceutically acceptable salts” include, but are notlimited to, water-soluble and water-insoluble salts. In one embodiment,the salt is of a base. The salt can be of a base selected from, e.g.,alkali metal salt bases such as sodium, lithium, or potassium salt basesand organic bases, such as ammonium, mono-, di-, and trimethylammonium,mono-, di- and triethylammonium, mono-, di- and tripropylammonium,ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,benzylammonium, dibenzylammonium, piperidinium, morpholinium,pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-,di- and triethanol-ammonium, ethyl diethanolammonium,n-butylmonoethanolammonium, tris(hydroxymethyl)methyl-ammonium,phenylmonoethanolammonium bases, among others. In another embodiment,the salt is of an acid. The salt can be of an acid selected from, e.g.,acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic,malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic,benzenesulfonic, toluenesulfonic, trifluoroacetic, camphorsulfonic,among others. Optionally, a composition of the invention may containboth a pharmaceutically acceptable salt and the free base form of acompound of the invention.

Prodrugs of compounds of formulae (I-III) may be used to modulate thepharmacokinetic properties, using various methods known to those skilledin the art. See, e.g., Jarkko Rautio et al., Nature Reviews DrugDiscovery, 7:255-270 (2008), which is hereby incorporated by reference.In the case of drugs containing an amine moiety such as when R² isCH₂NH₂, a variety of prodrug approaches have been reviewed by A. L.Simplicio, Molecules, 13:519-547 (2008), which is hereby incorporated byreference. More specifically, (alkoxycarbonyloxy)alkyl carbamates,(acyloxy)alkyl carbamates, and (oxodioxolenyl)alkyl carbamates have beenreported as effective prodrug strategies for amines by Zhong Li, Bioorg.Med. Chem. Lett., 7:2909-2912 (1997); J. Alexander, J. Med. Chem.,34:78-81 (1991); J. Alexander, J. Med. Chem., 31:318-322 (1988); and J.Alexander, J. Med. Chem., 39:480-486 (1996), all of which areincorporated by reference herein. In one embodiment, the prodrug is anamide of formulae (I-III). In one embodiment, when R² is CH₂NH₂, theamide is

C(O)(C₁₋₆alkyl), wherein C₁₋₆alkyl can be optionally substituted. Inanother embodiment, the prodrug is an ester of formulae (I-III). In oneembodiment, when R² is CH₂OH, the ester of it is

C(O)(C₁₋₆alkyl), wherein C₁₋₆alkyl can be optionally substituted.

In a further embodiment, a compound of the invention may be a solvate.As used herein, “solvate” does not significantly alter the physiologicalactivity or toxicity of the compounds, and as such may function aspharmacological equivalents to non-solvate compounds of the invention.The term “solvate” as used herein is a combination, physical associationand/or solvation of a compound of the present invention with a solventmolecule. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instances,the solvate can be isolated, such as when one or more solvent moleculesare incorporated into the crystal lattice of a crystalline solid. Thus,“solvate” encompasses both solution-phase and isolatable solvates. Ahydrate is a special form of solvate which includes water combined in adefinite ratio as water of crystallization.

Compounds described herein may contain an asymmetric center and may thusexist as enantiomers. Where the compounds according to the inventionpossess two or more asymmetric centers, they may exist as diastereomers.When bonds to the chiral center are depicted as straight lines in theformula of the invention, it is understood that both the (R) and (S)configurations, and hence both enantiomers and mixtures thereof, areembraced. The present invention includes all such possiblestereoisomers, unless the specific stereochemistry is specificallyindicated. It is well known in the art how to prepare substantially purestereoisomer, such as by resolution of racemic forms or by synthesisfrom optically active starting materials. In one embodiment, thecompound of formulae (I-III) is a substantially pure stereoisomer.“Substantially pure stereoisomer” refers to a stereoisomer form is atleast 95% pure with respect to other stereoisomers of otherwise the samestructure.

The following definitions are used in connection with the compoundsdescribed herein. In general, the number of carbon atoms present in agiven group is designated “C_(x-y)”, where x and y are the lower andupper limits, respectively. The carbon number as used in the definitionsherein refers to carbon backbone and carbon branching, but does notinclude carbon atoms of the substituents, such as alkoxy substitutionsand the like. Unless indicated otherwise, the nomenclature ofsubstituents that are not explicitly defined herein are determined bynaming from left to right the terminal portion of the functionalityfollowed by the adjacent functionality toward the point of attachment.As used herein, “optionally substituted” means that at least onehydrogen atom on the designated atom such as carbon or nitrogen atom isoptionally replaced by other substituents, provided that the normalvalence of the designated atom is not exceeded, and that thesubstitution results in a stable compound. When more than onesubstituent is present on an atom or group, the chosen substituents areindependent of each other (i.e., same or different).

“Alkyl” refers to a hydrocarbon chain that may be linear or branchedalkyl radical. In one embodiment, “C₁₋₇alkyl” means an alkyl thatcontains 1 to 7 (inclusive) carbon atoms. In another embodiment,“C₁₋₆alkyl” means an alkyl that contains 1 to 6 (inclusive) carbonatoms. In yet another embodiment, “C₁₋₄alkyl” means an alkyl containing1 to 4 (inclusive) carbon atoms. Examples of alkyl groups that arehydrocarbon chains include, but are not limited to, methyl, ethyl,propyl, butyl, pentyl, hexyl, and heptyl, where all isomers of theseexamples are contemplated.

“Substituted alkyl” refers to an alkyl group, as defined above, that issubstituted with the groups including, without limitation, one or moreF, one or two Cl, one or two OH, one amino group, one (C₁₋₆alkyl)aminogroup (i.e., C₁₋₆alkyl-NH—), one (di-C₁₋₆alkyl)amino group (i.e.,(alkyl)₂N—), one or two C₁₋₆alkoxy groups, one —NH—C(O)—C₁₋₆alkyl group,one —C(O)—NH₂ group, one —C(O)—NH—(C₁₋₆alkyl) group, one—C(O)—N—(C₁₋₆alkyl)₂ group, or one cyano group, or any combination ofthese substituents. “Substituted” means that one or more of the alkylgroup's hydrogen atoms is replaced with a substituent group as listedabove.

“Hydroxyalkyl” refers to -(alkyl)OH, where the alkyl is optionallysubstituted and is defined above. The OH moiety of the hydroxyalkyl maybe bound to any carbon atom, for example, any one of the internal carbonatoms or the terminal carbon atom of a hydrocarbon alkyl chain. Examplesof hydroxyalkyl include, but are not limited to, —CH₂OH, —CH₂CH₂OH,—CH(OH)CH₃, —CH₂CH₂CH₂OH, —CH₂CH(OH)CH₃, —CH(OH)CH₂CH₃, —C(OH)(CH₃)₂,-(2-hydroxy)-cyclopentyl, (3-hydroxy)-cyclobutyl, and the like.

“C₃₋₁₀cycloalkyl” refers to a saturated cyclic alkyl group which may bemonocyclic, bicyclic, polycyclic, or a fused/bridged ring system having3 to 10 carbon atoms. Exemplary cycloalkyl groups include, but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. Typical bridged cycloalkylsinclude, but are not limited to adamantyl, noradamantyl,bicyclo[1.1.0]butanyl, norbornyl(bicyclo[2.2.1]heptanyl), and the like.C₃₋₁₀cycloalkyl can be unsubstituted or substituted with one or more ofgroups including, without limitation, hydroxyl, halogen, or C₁₋₆alkyl.

“C₄₋₁₀cycloalkenyl” refers to an unsaturated or partially saturatednon-aromatic cyclic alkyl group which may be monocyclic, bicyclic,polycyclic, or a fused/bridged ring system having 4 to 10 carbon atoms.Exemplary cycloalkyl groups include, but not limited to cyclobutene,cyclopentene, cyclohexene, cyclohexa-1,4-diene, and the like.

“C₂₋₆alkenl” refers to a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical of two to six carbon atomscontaining at least one double bond. Exemplary cycloalkenyl groupsinclude, but not limited to ethenyl, propenyl, and the like.

“C₂₋₆alkynl” refers to a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical of two to six carbon atomscontaining at least one triple bond. Exemplary cycloalkyl groupsinclude, but not limited to ethynyl, propynyl, and the like.

“Alkoxy” refers to (alkyl)O, where the alkyl is optionally substitutedand is defined above. Examples of alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, and butoxy. The alkyl radical of an alkoxygroup can be unsubstituted or substituted as defined above.

“Aryl” refers to a monocyclic, bicyclic or polycyclic aromatichydrocarbon group containing carbon atoms. In one embodiment, arylcontains 6-12 carbon atoms. In one embodiment, the aryl is phenyl. Inone embodiment, the aryl is an aromatic or partly aromatic bicyclicgroup. In another embodiment, the aryl is naphthyl (such as α-naphthylor β-naphthyl), 1,2,3,4-tetrahydronaphthyl, or indanyl. An aryl groupcan be unsubstituted or substituted with one or more of groupsincluding, without limitation, halogen, C₁₋₆alkyl, C₂₋₆alknyl, CN,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl, C₁₋₆alkyl-N—(C₁₋₆alkyl)₂,—C₁₋₆alkyl-NH—C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogens, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl. In oneembodiment, an aryl group can be substituted with one or more of groupsincluding, without limitation, halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, wherein theheterocyclyl or heteroaryl is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, C(O)—C₁₋₆alkyl, or 4- to6-membered heterocyclyl.

“Substituted phenyl” refers to a phenyl group that is substituted withone or more of groups including, without limitation, halogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, CN, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogens, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl. In oneembodiment, a phenyl group can be substituted with one or more of groupsincluding, without limitation, halogen, CN, C₂₋₆alknyl, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl),—O-phenyl, —O—C₁₋₆alkyl-(4- to 6-membered heterocyclyl), C₁₋₆alkyl,hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl, wherein the heterocyclyl orheteroaryl is unsubstituted or substituted with 1-3 substituentsselected from halogen, C₁₋₆alkyl, C(O)—C₁₋₆alkyl, or 4- to 6-memberedheterocyclyl.

“Halogen” refers to F, Cl, Br or I.

“Heteroaryl” refers to a monocyclic, bicyclic or polycyclic aromatic orpartially aromatic ring system having one to three heteroatoms orheterogroups selected from O, N, S, S(═O), S(═O)₂, or C(═O). “Partiallyaromatic” refers to multi-cyclic fused ring groups where at least onebut not all rings are aromatic, such as a benzodioxole group. In oneembodiment, heteroaryl is a 5- to 10-membered ring system. In anotherembodiment, heteroaryl is a 5- to 6-membered ring system. Exemplaryheteroaryl ring groups include, but not limited to, furanyl, oxazolyl,isoxazolyl, isothiazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl,pyridinyl, pyrimidinyl, thiazinyl, pyrazinyl, pyrazolyl, pyrrolyl,tetrazolyl, imidazothiazolyl, oxadiazolyl, indolizidinyl, indolinyl,indazolyl, chromanyl, oxoindolinyl, indolyl, oxoindolyl, quinolinyl,3,4-dihydroisoquinolin-2(1H)-yl, quinoxalinyl, benzofuranyl,benzoxazolyl, benzo[d]isoxazolyl, benzo[d]thiazolyl,benzo[d][1,3]dioxolyl, 1H-benzo[d][1,2,3]triazolyl, 2H-indazolyl,1H-indazolyl, quinoxalin-2-yl, 1H-benzo[d]imidazolyl,pyrazolo[1,5-a]pyridinyl, dihydrobenzo[b][1,4]dioxinyl,(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl),4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl),5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, Hexahydropyrrolo [1,2-a]pyrazin-2(1H)-yl, 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazinyl,pyrazolo[1,5a]pyridinyl and the like.

“Substituted heteroaryl” refers to a heteroaryl group, as defined above,that is substituted with one or more of groups including, withoutlimitation, halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,—C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl. In oneembodiment, a heteroaryl group can be substituted with one or more ofgroups including, without limitation, halogen, C₁₋₆alkyl, NH₂,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl. In one embodiment, a heteroarylgroup can be substituted with one or more of groups including, withoutlimitation, halogen, CN, —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl,—C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂, —O—C₁₋₆alkyl-NH—(C₁₋₆alkyl),—O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to 6-membered heterocyclyl, —C(O)-(4- to6-membered heterocyclyl), —O-phenyl, —O—C₁₋₆alkyl-(4- to 6-memberedheterocyclyl), C₁₋₆alkyl, hydroxyl, C₁₋₆alkoxyl, or hydroxyC₁₋₆alkyl,wherein the heterocyclyl or heteroaryl is unsubstituted or substitutedwith 1-3 substituents selected from halogen, C₁₋₆alkyl, C(O)—C₁₋₆alkyl,or 4- to 6-membered heterocyclyl.

“Heterocycle” or “heterocyclyl” refers to a monocyclic, bicyclic orpolycyclic saturated ring system having one to three heteroatoms orheterogroups selected from O, N, S, S(═O), S(═O)₂, or C(═O). Amonocyclic heterocycle can be a 4- to 10-membered ring, whereas abicyclic heterocycle contains two fused or bridged 4- to 6-memberedrings having 5 to 10 ring atoms. Exemplary heterocyclyl groups include,but are not limited to, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl (thiolanyl), piperidinyl,piperazinyl, tetrahydropyranyl, tetrahydro-2H-pyranyl, morpholinyl,thiomorpholinyl, dioxanyl, 2,5-diazabicyclo[2.2.1]heptane,2,5-diazabicyclo[2.2.2]octane, and the like.

“Substituted heterocycle” or “substituted heterocyclyl” refers to aheterocycle or heterocyclyl group that is substituted with one or moreof groups including, without limitation, halogen, CN, —C(O)—NH₂,—C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆alkyl)₂, —O—C₁₋₆alkyl-NH₂,—O—C₁₋₆alkyl-NH—(C₁₋₆alkyl), —O—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, 4- to6-membered heterocyclyl, —C(O)-heterocyclyl, —O-phenyl, —O—C₁₋₆alkyl-(4-to 6-membered heterocyclyl), C₁₋₆alkyl, hydroxyl, C₁₋₆alkoxyl, orhydroxyC₁₋₆alkyl, wherein the heterocyclyl or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₆alkyl, C(O)—C₁₋₆alkyl, or 4- to 6-membered heterocyclyl. Inone embodiment, a heterocyclyl group can be substituted with one or moreof groups including, without limitation, halogen, C₁₋₆alkyl, NH₂,hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl. In one embodiment, a heterocyclylgroup can be substituted with one or more of groups including, withoutlimitation, hydroxyl, halogen, or C₁₋₆alkyl.

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The words “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusively.

As used herein, the term “about” means a variability of 10% from thereference given, unless otherwise specified.

A “patient” or “subject” is a mammal, e.g., a human or a veterinarypatient or subject, e.g., mouse, rat, guinea pig, dog, cat, horse, cow,pig, or non-human primate, such as a monkey, chimpanzee, baboon orgorilla.

The term “treating” or “treatment” is meant to encompass administeringto a subject a compound of the present invention for the purposes ofamelioration of one or more symptoms of a disease or disorder, includingpalliative care. A “therapeutically effective amount” refers to theminimum amount of the active compound which effects treatment.

Pharmaceutical compositions useful herein contain at least one or moreof compounds of formulae (I)-(III), or pharmaceutically acceptablesalts, prodrugs, solvates, hydrates, or stereoisomers thereof in apharmaceutically acceptable carrier optionally with otherpharmaceutically inert or inactive ingredients. In another embodiment, acompound of formulae (I-III) is present in a single composition. In afurther embodiment, a compound of formulae (I-III) is combined with oneor more excipients and/or other therapeutic agents as described below.

The pharmaceutical compositions of the invention comprise an amount ofat least one or more of compounds of formulae (I-III) orpharmaceutically acceptable salts, prodrugs, solvates, hydrates, orstereoisomers thereof that is effective for treating a conditiontreatable by inhibiting ERK1/2 in a subject in need thereof.Specifically, the dosage of the compound of formulae (I-III) to achievea therapeutic effect will depend on the formulation, age, weight and sexof the patient and route of delivery. It is also contemplated that thetreatment and dosage of the compound of formulae (I-III) may beadministered in unit dosage form and that one skilled in the art wouldadjust the unit dosage form accordingly to reflect the relative level ofactivity. The decision as to the particular dosage to be employed (andthe number of times to be administered per day) is within the discretionof the ordinarily-skilled physician, and may be vaned by titration ofthe dosage to the particular circumstances to produce the desiredtherapeutic effect. In one embodiment, the therapeutically effectiveamount is about 0.01 mg/kg to 10 mg/kg body weight. In anotherembodiment, the therapeutically effective amount is less than about 5g/kg, about 500 mg/kg, about 400 mg/kg, about 300 mg/kg, about 200mg/kg, about 100 mg/kg, about 50 mg/kg, about 25 mg/kg, about 10 mg/kg,about 1 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about100 μg/kg, about 75 μg/kg, about 50 μg/kg, about 25 μg/kg, about 10μg/kg, or about 1 μg/kg. However, the therapeutically effective amountof the compound of formulae (I-III) can be determined by the attendingphysician and depends on the condition treated, the compoundadministered, the route of delivery, the age, weight, severity of thepatient's symptoms and response pattern of the patient.

The therapeutically effective amounts may be provided on regularschedule, i.e., daily, weekly, monthly, or yearly basis or on anirregular schedule with varying administration days, weeks, months, etc.Alternatively, the therapeutically effective amount to be administeredmay vary. In one embodiment, the therapeutically effective amount forthe first dose is higher than the therapeutically effective amount forone or more of the subsequent doses. In another embodiment, thetherapeutically effective amount for the first dose is lower than thetherapeutically effective amount for one or more of the subsequentdoses. Equivalent dosages may be administered over various time periodsincluding, but not limited to, about every 2 hours, about every 6 hours,about every 8 hours, about every 12 hours, about every 24 hours, aboutevery 36 hours, about every 48 hours, about every 72 hours, about everyweek, about every two weeks, about every three weeks, about every month,and about every two months. The number and frequency of dosagescorresponding to a completed course of therapy will be determinedaccording to the judgment of a health-care practitioner. Thetherapeutically effective amounts described herein refer to totalamounts administered for a given time period; that is, if more than onecompound of formulae (I-III) or a pharmaceutically acceptable salt,prodrug or solvate thereof is administered, the therapeuticallyeffective amounts correspond to the total amount administered.

The pharmaceutical compositions containing a compound of formulae(I-III) may be formulated neat or with one or more pharmaceuticalcarriers for administration. The amount of the pharmaceutical carrier(s)is determined by the solubility and chemical nature of the compound offormulae (I-III), chosen route of administration and standardpharmacological practice. The pharmaceutical carrier(s) may be solid orliquid and may incorporate both solid and liquid carriers. A variety ofsuitable liquid carriers is known and may be readily selected by one ofskill in the art. Such carriers may include, e.g., DMSO, saline,buffered saline, hydroxypropylcyclodextrin, and mixtures thereof.Similarly, a variety of solid carriers and excipients are known to thoseof skill in the art. The compounds of formulae (I-III) may beadministered by any route, taking into consideration the specificcondition for which it has been selected. The compounds of formulae(I-III) may, be delivered orally, by injection, inhalation (includingorally, intranasally and intratracheally), ocularly, transdermally,intravascularly, subcutaneously, intramuscularly, sublingually,intracranially, epidurally, rectally, and vaginally, among others.

Although the compound of formulae (I-III) may be administered alone, itmay also be administered in the presence of one or more pharmaceuticalcarriers that are physiologically compatible. The carriers may be in dryor liquid form and must be pharmaceutically acceptable. Liquidpharmaceutical compositions are typically sterile solutions orsuspensions. When liquid carriers are utilized for parenteraladministration, they are desirably sterile liquids. Liquid carriers aretypically utilized in preparing solutions, suspensions, emulsions,syrups and elixirs. In one embodiment, the compound of formulae (I-III)is dissolved a liquid carrier. In another embodiment, the compound offormulae (I-III) is suspended in a liquid carrier. One of skill in theart of formulations would be able to select a suitable liquid carrier,depending on the route of administration. The compound of formulae(I-III) may alternatively be formulated in a solid carrier. In oneembodiment, the composition may be compacted into a unit dose form,i.e., tablet or caplet. In another embodiment, the composition may beadded to unit dose form, i.e., a capsule. In a further embodiment, thecomposition may be formulated for administration as a powder. The solidcarrier may perform a variety of functions, i.e., may perform thefunctions of two or more of the excipients described below. For example,solid carrier may also act as a flavoring agent, lubricant, solubilizer,suspending agent, filler, glidant, compression aid, binder,disintegrant, or encapsulating material.

The composition may also be sub-divided to contain appropriatequantities of the compound of formulae (I-III). For example, the unitdosage can be packaged compositions, e.g., packeted powders, vials,ampoules, prefilled syringes or sachets containing liquids.

Examples of excipients which may be combined with one or more compoundof formulae (I-III) include, without limitation, adjuvants,antioxidants, binders, buffers, coatings, coloring agents, compressionaids, diluents, disintegrants, emulsifiers, emollients, encapsulatingmaterials, fillers, flavoring agents, glidants, granulating agents,lubricants, metal chelators, osmo-regulators, pH adjustors,preservatives, solubilizers, sorbents, stabilizers, sweeteners,surfactants, suspending agents, syrups, thickening agents, or viscosityregulators. See, for example, the excipients described in the “Handbookof Pharmaceutical Excipients”, 5^(th) Edition, Eds.: Rowe, Sheskey, andOwen, APhA Publications (Washington, D.C.), Dec. 14, 2005, which isincorporated herein by reference.

In one embodiment, the compositions may be utilized as inhalants. Forthis route of administration, compositions may be prepared as fluid unitdoses using a compound of formulae (I-III) and a vehicle for delivery byan atomizing spray pump or by dry powder for insufflation.

In another embodiment, the compositions may be utilized as aerosols,i.e., oral or intranasal. For this route of administration, thecompositions are formulated for use in a pressurized aerosol containertogether with a gaseous or liquefied propellant, e.g.,dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and thelike. Also provided is the delivery of a metered dose in one or moreactuations.

In another embodiment, the compositions may be administered by asustained delivery device. “Sustained delivery” as used herein refers todelivery of a compound of formulae (I-III) which is delayed or otherwisecontrolled. Those of skill in the art know suitable sustained deliverydevices. For use in such sustained delivery devices, the compound offormulae (I-III) is formulated as described herein.

In addition to the components described above for use in the compositionand the compound of formulae (I-III), the compositions and kitsdescribed herein may contain one or more medications or therapeuticagents. In one embodiment, the compositions and kits described hereinmay contain one or more medications or therapeutic agents which are usedto treat cancers, including, e.g., cancers characterized by tumors,including solid tumors, and “liquid” or non-solid tumor cancers (e.g.,lymphoma). In one embodiment, the medication is a chemotherapeutic.Examples of chemotherapeutics include those recited in the “Physician'sDesk Reference”, 64^(th) Edition, Thomson Reuters, 2010, which is herebyincorporated by reference. Therapeutically effective amounts of theadditional medication(s) or therapeutic agents are well known to thoseskilled in the art. However, it is well within the attending physicianto determine the amount of other medication to be delivered.

The compounds of formulae (I-III) and/or other medication(s) ortherapeutic agent(s) may be administered in a single composition.However, the present invention is not so limited. In other embodiments,the compounds of formulae (I-III) may be administered in one or moreseparate formulations from other compounds of formulae (I-III),chemotherapeutic agents, or other agents as is desired.

Also provided herein are kits or packages of pharmaceutical formulationscontaining the compounds of formulae (I-III) or compositions describedherein. The kits may be organized to indicate a single formulation orcombination of formulations to be taken at each desired time.

Suitably, the kit contains packaging or a container with the compound offormulae (I-III) formulated for the desired delivery route. Suitably,the kit contains instructions on dosing and an insert regarding theactive agent. Optionally, the kit may further contain instructions formonitoring circulating levels of product and materials for performingsuch assays including, e.g., reagents, well plates, containers, markersor labels, and the like. Such kits are readily packaged in a mannersuitable for treatment of a desired indication. For example, the kit mayalso contain instructions for use of a spray pump or other deliverydevice. Other suitable components to include in such kits will bereadily apparent to one of skill in the art, taking into considerationthe desired indication and the delivery route.

The compounds of formulae (I-III) or compositions described herein canbe a single dose or for continuous or periodic discontinuousadministration. For continuous administration, a package or kit caninclude the compound of formulae (I-III) in each dosage unit (e.g.,solution, lotion, tablet, pill, or other unit described above orutilized in drug delivery), and optionally instructions foradministering the doses daily, weekly, or monthly, for a predeterminedlength of time or as prescribed. When the compound of formulae (I-III)is to be delivered periodically in a discontinuous fashion, a package orkit can include placebos during periods when the compound of formulae(I-III) is not delivered. When varying concentrations of a composition,of the components of the composition, or the relative ratios of thecompounds of formulae (I-III) or agents within a composition over timeis desired, a package or kit may contain a sequence of dosage unitswhich provide the desired variability.

A number of packages or kits are known in the art for dispensingpharmaceutical agents for periodic oral use. In one embodiment, thepackage has indicators for each period. In another embodiment, thepackage is a labeled blister package, dial dispenser package, or bottle.

The packaging means of a kit may itself be geared for administration,such as an inhalant, syringe, pipette, eye dropper, or other suchapparatus, from which the formulation may be applied to an affected areaof the body, such as the lungs, injected into a subject, or even appliedto and mixed with the other components of the kit.

The compositions of these kits also may be provided in dried orlyophilized forms. When reagents or components are provided as a driedform, reconstitution generally is by the addition of a suitable solvent.It is envisioned that the solvent also may be provided in anotherpackage.

The kits of the present invention also will typically include a meansfor containing the vials in close confinement for commercial sale suchas, e.g., injection or blow-molded plastic containers into which thedesired vials are retained. Irrespective of the number or type ofpackages and as discussed above, the kits also may include, or bepackaged with a separate instrument for assisting with theinjection/administration or placement of the composition within the bodyof an animal. Such an instrument may be an inhalant, syringe, pipette,forceps, measuring spoon, eye dropper or any such medically approveddelivery means.

In one embodiment, a kit is provided and contains a compound of formulae(I-III). The compound of formulae (I-III) may be in the presence orabsence of one or more of the carriers or excipients described above.The kit may optionally contain instructions for administering themedication and the compound of formulae (I-III) to a subject having adisease characterized by the dysregulation of the RAS/RAF/MEK/ERKpathway.

In a further embodiment, a kit is provided and contains a compound offormulae (I-III) in a second dosage unit, and one or more of thecarriers or excipients described above in a third dosage unit. The kitmay optionally contain instructions for administering the medication andthe compound of formulae (I-III) to a subject having a diseasecharacterized by the dysregulation of the RAS/RAF/MEK/ERK pathway.

The compounds described herein are useful in regulating conditions whichare associated with the RAS/RAF/MEK/ERK pathways. In one embodiment,such a disease is associated with abnormal cellular proliferation. Theterm “abnormal cellular proliferation” refers to the uncontrolled growthof cells which are naturally present in a mammalian body. In oneembodiment, a disease which is characterized by abnormal cellularproliferation is cancer, including, without limitation, cancer of theprostate, head, neck, eye, mouth, throat, esophagus, bronchus, larynx,pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus,cervix, breast, ovaries, vagina, testicles, skin, thyroid, blood, lymphnodes, kidney, liver, intestines, pancreas, brain, central nervoussystem, adrenal gland, skin or a leukemia or lymphoma. In oneembodiment, the disease characterized by abnormal cellular proliferationis melanoma skin cancer or cancer of the lung, colon, breast orprostate. In another embodiment, the abnormal cellular proliferation isassociated with either solid tumor or hematological cancer.

The term “regulation” or variations thereof as used herein refers to theability of a compound of formulae (I-III) to inhibit one or morecomponents of a biological pathway. In one embodiment, “regulation”refers to inhibition ERK1/2 activity. In yet another embodiment,regulation includes inhibition of the RAS/RAF/MEK/ERK pathway.

The activity of compounds of formulae (I-III) was established inmultiple in vitro and in vivo assays. For example, compounds of theinvention were demonstrated to cause inhibition of ERK1 and ERK2enzymatic activities in biochemical assays using a homogeneous timeresolved fluorescence (HTRF) technique; representative data are providedin Table 2. Furthermore, compounds of the invention were found to beactive in a cell-based mechanistic assay; that is, compounds of theinvention were demonstrated to inhibit phosphorylation of RSK1(S380)(the downstream protein target of ERK1/2) by an enzyme-linkedimmunosorbent assay (ELISA) method. Representative data are provided inTable 2. The functional utility of compounds of formulae (I-III) wasdemonstrated by their activity in in vitro tumor cell proliferationassays in a panel of tumor cell lines with mutations in theRAS/BRAF/MEK/ERK pathway; representative data are again provided inTable 2. The compounds of formulae (I-III) exhibit ERK1/2 inhibitoryactivity, and therefore can be utilized in order to inhibit abnormalcell growth in which the RAS/RAF/MEK/ERK pathway plays a role. Thus, thecompounds of formulae (I-III) are effective in the treatment ofdisorders with which abnormal cell growth actions of RAS/RAF/MEK/ERKdysregulation are associated, such as cancer. One of skill in the artwould recognize that there is an established link between activity intumor cell proliferation assays in vitro and anti-tumor activity in theclinical setting. For example, the therapeutic utility of a variety ofpharmaceutical agents, e.g, taxol (Silvestrini, Stem Cells, 1993,11(6):528-535), taxotere (Bissery, Anti Cancer Drugs, 1995, 6(3):330)and topoisomerase inhibitors (Edelman, Cancer Chemother. Pharmacol.,1996, 37(5):385-39), has been demonstrated by using in vitro tumorproliferation assays.

Finally, compounds of formulae (I-III) were demonstrated to inhibit invivo tumor growth upon dosing the compounds in human tumor xenograftmodels, such as the A375 human melanoma xenograft model harboring B-RAFV600E mutation, the HT-29 human colon cancer xenograft model harboringB-RAF V600E mutation, the HCT116 human colon cancer xenograft modelharboring KRAS mutation, the A549 human lung carcinoma xenograft modelharboring KRAS mutation, and the BxPC3 human pancreatic carcinomaxenograft model. The compounds were also demonstrated to inhibit thelevel of phospho-RSK in the tumors in the A375 xenograft model, upontreatment with compounds; this indicates effective inhibition of thetarget proteins ERK1/2 in vivo by compounds of the invention. One ofskill in the art would recognize that there is an established linkbetween activity in human tumor xenograft models and anti-tumor activityin the clinical setting.

Compounds of formulae (I-III) that have particularly promising utilitycan be identified by using the assays as described herein. For example,compounds of formulae (I-III) that are found to exhibit IC₅₀ values lessthan 100 nM in the ERK1/2 biochemical assays, and IC₅₀ values less than500 nM in the phospho-RSK1 and cell proliferation assays, and causing40% or greater tumor growth inhibition in one or more human tumorxenograft models, would be identified as particularly useful compoundsof the invention.

In one embodiment, methods for regulating the RAS/RAF/MEK/ERK pathwayare provided and include administering a therapeutically effectiveamount of a compound of formulae (I-III) to a patient in need thereof.

In a further embodiment, methods for inhibiting ERK1/2 are provided andinclude administering a therapeutically effective amount of a compoundof formulae (I-III) to a patient in need thereof.

In another desirable embodiment, methods for treating a diseasecharacterized by an abnormal cellular growth resulting from adysregulated RAS/RAF/MEK/ERK pathway are provided and includeadministering of a therapeutically effective amount of a compound offormulae (I-III) to a patient in need thereof.

In a further desirable embodiment, methods for treating a conditiontreatable by inhibiting ERK1/2 are provided and include administering atherapeutically effective amount of a compound of formulae (I-III) to apatient in need thereof.

As described herein, “a therapeutically effective amount” of a compoundwhen used for the treatment of a condition is an amount that at leastslows the progression of the condition. “A therapeutically effectiveamount” of a compound when used for the treatment of cancer is an amountwhich may slow the progression of cancer, reduce the number of cancercells in fluids (e.g., blood, peripheral cells or lymphatic fluids),reduce tumor size, inhibit metastasis, inhibit tumor growth and/orameliorate one or more of the symptoms of the cancer. For cancertherapy, efficacy can be measured for example, by assessing the time todisease progression and/or determining the response rate.

Process for Preparing the Compounds

Methods useful for preparing the compounds of formulae (I-III) are setforth in the Examples and generalized in the Schemes below. One of skillin the art will recognize that the schemes can be adapted to produceother compounds and their pharmaceutically acceptable salts, prodrugs,solvates, hydrates, or stereoisomers of formulae (I-III).

In the following reactions described to prepare compounds describedherein, it can be necessary to protect reactive functional groups, forexample hydroxyl, amino, imino, thio or carboxyl groups, which aredesired in the final product, to avoid their unwanted participation inthe reactions. Conventional protecting groups can be used in accordancewith standard practices, for example, see Green et al., ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1991.

The below schemes outline the syntheses of the compounds of formulae(I-III). The examples following those are illustrated as representativesprepared in each scheme, and should not be construed as limiting thescope of the present invention.

The following abbreviations are used and have the indicated definitions:MHz is megahertz (frequency), m is multiplet, t is triplet, d isdoublet, s is singlet, br is broad, CDCl₃ is deutero chloroform, calcdis calculated, min is minutes, h is hours, g is grams, mmol ismillimoles, mL is milliliters, N is Normal (concentration), M ismolarity (concentration), M is micromolar, ee is enantiomeric excess, °C. is degree centigrade, HPLC is High Performance Liquid Chromatography,LC-MS is Liquid Chromatography-Mass Spectroscopy, mp is melting point,NMR is Nuclear Magnetic Resonance, TLC is thin layer chromatography, THFis tetrahydrofuran, MeOH is methanol, DCM is dichloromethane, DMF isN,N-dimethyl formamide, DMSO is dimethyl sulfoxide, EtOH is ethylalcohol, EtOAc is ethyl acetate, MeOH is methanol, RT is roomtemperature, HCl is hydrogen chloride or hydrochloric acid, TFA istrifluoroacetic acid, EtMgBr is ethyl magnesium bromide, n-BuLi isn-butyl lithium, NaHCO₃ is sodium bicarbonate, Na₂CO₃ is sodiumcarbonate, Na₂SO₄ is sodium sulfate, NMP is N-methyl-2-pyrrolidone, EDCor EDC.HCl is N-(3-dimethylaminopropyl)-N-ethylcarbodiimidehydrochloride, TEA is triethylamine, DIPEA is diisopropylethylamine,HOBt is N-hydroxy-benzotriazole or N-hydroxy-benzotriazole hydrate, andT3P is propylphosphonic anhydride.

Schemes

Scheme 1 depicts one synthesis method to prepare compounds of formula(I) where M is NH, Z═N, X═N, J=—CH(R²)— or —CH(R²)CH₂—, R²═H, C₁₋₄alkyl,CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂, and Y═CH. In one embodiment,a 4-nitropyrazole [A] is reacted with a 2,4-dichloropyrimidine [B] toprovide a pyrazolyl-pyrimidine [C]. This reaction is performed in thepresence of a base, such as potassium carbonate, in a suitable solventsuch as acetone or dioxane. The reaction may be performed at elevatedtemperatures up to the reflux temperature of the solvent. Intermediate[C] is then reacted with an amine R⁴—NH₂ to provide the intermediate[D]. This coupling reaction may be performed in the presence of apalladium catalyst such as Pd₂(dba)₃[tris(dibenzylideneacetone)dipalladium(0)], BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl), and potassium carbonate,in a suitable solvent such as dioxane. The reaction may be performed atelevated temperatures, for example in dioxane at 90° C. in a sealedglass tube. Reduction of the nitro moiety in [D] then provides theamino-pyrazolyl intermediate [E]. This reduction process can be carriedout by reaction with zinc powder and ammonium chloride in a solvent suchas THF:methanol (2:1), at a temperature such as 0° C. to 25° C. Theamine intermediate [E] is then reacted with an amine [F] to form acompound of the invention, namely the urea (I-A). This coupling reactioncan be performed using CDI (1,1′-carbonyldiimidazole) in a solvent suchas THF. The reaction may be performed at elevated temperatures, forexample in THF at 85° C. to 120° C. with microwave radiation. Thiscoupling reaction can also be carried out by using 4-nitrophenylchloroformate, pyridine and DIPEA (diisopropylethylamine) instead ofCDI.

Scheme 2 depicts another synthesis method to prepare compounds offormula (I), where in this example M is NH, Z═N, X═N, J=—CH(R²)— or—CH(R²)CH₂—, R²═H, C₁₋₄alkyl, CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂,and Y═CH. In this method, intermediate [C] is prepared as described inScheme 1, and then a reduction process is carried out to provideamino-pyrazole [G]. This reduction process can be carried out byreaction with zinc powder and ammonium chloride in a solvent such asTHF:methanol (2:1), at a temperature such as 0° C. to 25° C. The amineintermediate [G] is then reacted with an amine [F] to form a ureaintermediate [H]. This reaction can be carried out by using4-nitrophenyl chloroformate, pyridine and DIPEA (diisopropylethylamine)in a suitable solvent such as DCM (dichloromethane), at a temperaturesuch as 0° C. to 25° C. The intermediate [H] is then reacted with anamine R⁴—NH₂ to provide a compound of the invention (I-A). This couplingreaction may be performed in the presence of a palladium catalyst suchas Pd₂(dba)₃, BINAP, and potassium carbonate, in a suitable solvent suchas dioxane. The reaction may be performed at elevated temperatures, forexample in dioxane at 90° C. in a sealed glass tube. An alternativemethod for the last step is to react the intermediate [H] with an amineR⁴—NH₂ in ethanol or isopropanol, optionally in the presence of DIPEA,with heating in a sealed glass tube.

Scheme 3 depicts one synthesis method to prepare compounds of formula(I), where in this example M is a bond, Z═N, J=—CH(R²)— or —CH(R²)CH₂—,R²═H, C₁₋₄alkyl, CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂, and Y═CR⁷.In this method, a 2, 4-dichloropyrimidine or 2-chloro-4-bromopyrimidine[B] is reacted with a heterocyclic ester [J] to form the intermediate[K]. The reaction can be carried out in the presence of a base, forexample potassium carbonate, in a suitable solvent such as acetonitrile.The reaction may be performed at elevated temperatures up to the refluxtemperature of the solvent. The intermediate [K] is then reacted with anamine R⁴—NH₂ to provide the intermediate [L]. This coupling reaction maybe performed in the presence of a palladium catalyst such as Pd₂(dba)₃,BINAP, and potassium carbonate, in a suitable solvent such as dioxane.The reaction may be performed at elevated temperatures, for example indioxane at 90° C. to 100° C. in a sealed glass tube. An alternativemethod to form the intermediate [L] is to react the intermediate [K]with an amine R⁴—NH₂ in ethanol or isopropanol, optionally in thepresence of DIPEA, with heating in a sealed glass tube. The ester moietyin intermediate [L] is hydrolyzed to provide the correspondingcarboxylic acid [M], for example by treatment with aqueous sodiumhydroxide or aqueous lithium hydroxide in a solvent such as methanol orTHF, at a temperature such as 0° C. to 50° C. The intermediate [M] isthen coupled with an amine [F] to form a compound of the invention,namely the amide (I-B). This amide-coupling reaction can be carried outby using the amide-coupling reagent EDC[1-ethyl-3-(3-dimethylaminopropyl)carbodiimide], optionally in thepresence of HOBt (1-hydroxybenzotriazole) and triethylamine, in asuitable solvent such as NMP (N-methyl-2-pyrrolidone). The reaction maybe performed at a temperature such as 0° C. to 25° C. This couplingreaction can alternatively be carried out by using any of several otheramide-coupling reagents that are known to those skilled in the art, forexample T3P (propylphosphonic anhydride).

Scheme 3a depicts a variation of Scheme 3, wherein the amide-couplingreaction with amine [F] is carried out first, followed by reaction withthe pyrimidine [B], and then reaction with the amine R⁴—NH₂ to provide acompound of the invention, namely the amide (I-B).

Scheme 4 depicts a synthesis method to prepare compounds of formula (I)where M is a bond, R² ═CH₂NH₂, Z═N, and X═CR⁷. In this method, a 2,4-dichloropyrimidine or 2-chloro-4-bromopyrimidine [B] is coupled with aheterocyclic ester [N] to form the intermediate [0], by a method similarto that described in Scheme 3 for the preparation of [K]. Reaction ofcompound [0] with an amine R⁴—NH₂ to form intermediate [P] is carriedout by methods similar to those described in Scheme 3 for thepreparation of [L]. Hydrolysis of the ester moiety in [P] to form thecorresponding carboxylic acid [Q] is achieved by methods similar tothose described in Scheme 3 for the preparation of [M]. The intermediate[Q] is then coupled with an amine [R] to form the amide [S], by usingamide-coupling methods such as those described for the preparation of(I-B) in Scheme 3. As an alternative, the ester intermediate [P] can beconverted directly to (S) by reaction with an amine [R], in the presenceof trimethylaluminum in a suitable solvent such as toluene. The reactionis carried out at a temperature such as 0° C. to 100° C., optionallyusing microwave radiation. Reduction of the nitrile moiety in [S] iscarried out to provide the corresponding amine (I-C), a compound of theinvention, by hydrogenation using Raney nickel in methanolic ammonia.The reaction is performed, for example, at 25 psi hydrogen for 16 hoursat about room temperature.

Scheme 5 depicts another method to synthesize compounds of formula (I),in this example where M is a bond, Z═N, J=—CH(R²)— or —CH(R²)CH₂—, R²═H,C₁₋₄alkyl, CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂, Y═N, and X═C—R⁷.In this method, an aldehyde building block [T] is reacted with a 2,4-dichloropyrimidine (or a 2-chloro-4-bromopyrimidine) to prepare thealdehyde intermediate [U], which is then converted to the correspondingcarboxylic acid intermediate [V] by methods known in the art. Theintermediate [V] is then coupled with an amine [F] by an amide-couplingmethod such as described in Scheme 3, to form the amide intermediate[W]. Reaction of [W] with an amine R⁴—NH₂, by methods such as thosedescribed for the formation of [L] in Scheme 3, provides a compound ofthe invention (I-D).

Scheme 6 depicts another method to synthesize compounds of formula (I),where M is a bond, Z═N, J=—CH(R²)— or —CH(R²)CH₂—, R²═H, C₁₋₄alkyl,CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂, and X═C—R⁷. In this method,the intermediate [X] is prepared by methods similar to those used toprepare intermediate [P] in Scheme 4. The ester intermediate [X] is thenreacted with an amine [F], in the presence of trimethylaluminum in asuitable solvent such as toluene. The reaction is carried out at atemperature such as 0° C. to 100° C., optionally using microwaveradiation, to provide a compound of the invention (I-E). This method hasparticular utility when R⁴ is optionally substituted alkyl.

Scheme 7 depicts a method for the preparation of compounds of formula(I), where in this example M is a bond, Z═CH, J=—CH(R²)— or —CH(R²)CH₂—,R²═H, C₁₋₄alkyl, CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂, and X═C—R⁷.In this method, a 2-amino-4-bromopyridine [Y] is reacted with an iodocompound R⁴—I in the presence of a palladium(0) catalyst, to provide thepyridine intermediate [Z]. Intermediate [Z] is then reacted with aheterocyclic ester [AA] to provide the intermediate [AB]. This reactionis conducted in a solvent such as DMF, in the presence of copper(I)iodide, L-proline and potassium phosphate, at a temperature such as 25°C. to 150° C. in a sealed glass tube. The ester moiety in theintermediate [AB] is hydrolyzed by methods such as those described forthe formation of [M] in Scheme 3, and then the carboxylic acidintermediate [AC] is reacted with [F] using an amide-coupling methodsuch as those described in Scheme 3, to provide a compound of theinvention (I-F). Alternatively, the ester intermediate [AB] can beconverted directly to (I-F) by using trimethylaluminum in a suitablesolvent such as toluene, using the method as described in Scheme 6.

Scheme 8 depicts a further method for the preparation of compounds offormula (I), where in this case M is a bond, Z═CH, J=—CH(R²)— or—CH(R²)CH₂—, R²═H, C₁₋₄alkyl, CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂,X═CH, and Y═CH. In this method, a 2-chloro-pyridine [AD] is oxidized,nitrated and then reacted with an amine R⁴—NH₂ to provide the4-nitro-pyridine N-oxide intermediate [AG]. The N-oxide and nitromoieties in [AG] are reduced and the resulting 4-amino group in [AH] isconverted to a bromide moiety. The 4-bromo-pyridine intermediate [AI] isthen reacted with an appropriate heterocycle such as the pyrrolederivative [AJ], to provide a compound of the invention (I-G).

Scheme 9 depicts a method for the preparation of compounds of formula(I), where in this example M is a bond, Z═CH, X═C—R⁷, J=—CH(R²)— andR²═CH₂NH₂. In this method, aspects of the general methods depicted inSchemes 4 and 7 are utilized and combined to provide a compound of theinvention (I-H).

Scheme 10 depicts a method for the preparation of compounds of formula(I), where in this example M is a bond, Z═CH, J=—CH(R²)— or —CH(R²)CH₂—,R²═H, C₁₋₄alkyl, CH₂OH, CH₂OC₁₋₆alkyl, or CH₂N(C₁₋₆alkyl)₂, R⁵═Cl,X═C—R⁷, and Y═N. In this method, 4-chloro-pyridine [AL] is converted inthree steps to 3,4-dichloro-pyridine [AO], which is then converted insubsequent steps using methods similar to those described in the schemesabove, to a compound of the invention (I-J).

Scheme 11 depicts a method for the preparation of compounds of formula(I), where in this example M is a bond, Z═CH, R²═CH₂NH₂, X═C—R⁷, andY═N. In this method, a 2,4-dichloro-pyridine or 2-chloro-4-bromopyridine[AT] is reacted with a heterocyclic ester [AQ], in the presence of abase such as potassium carbonate, in a suitable solvent such as DMF. Thereaction may be performed at room temperature to elevated temperaturessuch as 100° C. or the reflux temperature of the solvent. The2-chloro-pyridine intermediate [AU] is then reacted with an amine R⁴—NH₂to provide the intermediate [AV]. This coupling reaction may beperformed in the presence of a palladium catalyst such as Pd₂(dba)₃,BINAP, and potassium carbonate, in a suitable solvent such as dioxane.The reaction may be performed at elevated temperatures, for example indioxane at 90° C. in a sealed glass tube, or using microwave radiationat 100° C. The ester moiety of intermediate [AV] is then hydrolyzed toprovide the corresponding carboxylic acid [AW], for example by treatmentwith aqueous sodium hydroxide or aqueous lithium hydroxide in a solventsuch as methanol or THF, at a temperature such as 0° C. to 50° C. Thecarboxylic acid [AW] is then coupled with an amine [R] to form the amide[AX], by using amide-coupling methods such as those described for thepreparation of (I-B) in Scheme 3. Reduction of the nitrile moiety in[AX] is carried out to provide the corresponding amine (I-K), a compoundof the invention, by hydrogenation using Raney nickel in methanolicammonia. The reaction is performed, for example, at 15 psi to 25 psihydrogen for about 6 to 16 hours at about room temperature.

Scheme 12 depicts a method for the preparation of compounds of formula(I), where in this example M is a bond, Z═CH, X═N, and Y═N. In thismethod, a 2,4-dichloro-pyridine (or 2-chloro-4-bromopyridine) [AT] isreacted with sodium azide to provide the 4-azido-pyridine [AY], which isthen condensed with methyl propiolate to produce the triazoleintermediate [AZ]. The ester moiety in intermediate [AZ] is hydrolyzedby methods such as those described in Scheme 11 to give thecorresponding carboxylic acid, which is then reacted with an amine suchas [F] by using amide-coupling methods such as described in Scheme 10,or reacted with an amine such as [R] by using amide-coupling methods andthen reduced such as described in Scheme 11, to provide a compound ofthe invention (I-L).

Scheme 13 depicts a method for the preparation of compounds of formula(I), where in this example M is a bond, Z═CH, R⁵═H, and X═CR⁷. In thismethod, 2-fluoro-4-iodo-pyridine [BA] is reacted with an amine R⁴—NH₂ toprovide the intermediate [BB]. The reaction is carried out in a suitablesolvent such as DMF or NMP, and may be performed at elevatedtemperatures, for example at 90° C. to 100° C. in a sealed glass tube.The intermediate [BB] is then reacted with a heterocyclic ester [N] toprovide the intermediate [BC]. The reaction is conducted in a suitablesolvent such as DMF or NMP in the presence of L-proline, copper(I)iodide, and a base such as potassium carbonate, at a temperature rangingfrom 25° C. to elevated temperatures such as 100° C. to 150° C. in asealed glass tube. The ester moiety in the intermediate [BC] ishydrolyzed by methods such as those described in Scheme 11 to give thecorresponding carboxylic acid, which is then reacted with an amine suchas [F] by using amide-coupling methods such as described in Scheme 10,or reacted with an amine such as [R] by using amide-coupling methods andthen reduced such as described in Scheme 11, to provide a compound ofthe invention (I-M).

Methods useful for the preparation of synthesis building blocks used inthe synthesis of compounds of formula (I) are set forth in the schemesbelow. One of skill in the art will recognize that the schemes can beadapted to produce the other compounds of formula (I) andpharmaceutically acceptable salts, prodrugs, solvates, hydrates, orstereoisomers of compounds of formula (I).

Examples of methods useful for the preparation of compounds such as(I-N) and (I-O) that may act as prodrugs of compounds of formula (I) areset forth in the Schemes 18 and 19 below. One of skill in the art willrecognize that these schemes can be adapted to produce additionalcompounds that may act as prodrugs of compounds of formula (I).

Scheme 20 depicts a further method for the preparation of compounds offormula (I), where in this example M is a bond, R²═CH₂NH₂, Z═N, andX═CR⁷. This method provides an alternative to the method described inScheme 4. In this method, an amino-alcohol (in this example, a singleenantiomer) [BD] is converted by standard methods to the N-Boc protectedanalog [BE], and then the hydroxyl moiety is converted to thecorresponding methanesulfonate ester, for example by reaction withmethanesulfonyl chloride and triethylamine in a solvent such asdichloromethane. This methanesulfonate compound [BF] is then reactedwith sodium azide to form the corresponding azide derivative [BG]. Theazide reaction is carried out in a suitable solvent such as DMF or NMP,and may be performed at elevated temperatures, for example at about 50°C. The N-Boc group is then removed by standard methods, for example bytreatment with 4 M HCl in dioxane. The resulting amino azide compound[BH] is then coupled with intermediate [Q] to form the amide [BI], byusing amide-coupling methods such as those described for the preparationof (I-B) in Scheme 3. The azide moiety is reduced, for example byreaction with zinc dust and ammonium chloride in a solvent such asmethanol, to provide a compound of the invention (I-P), in this exampleas a single enantiomer.

EXAMPLES

All reactions were carried out under dry nitrogen and or argonatmosphere unless otherwise specified. Unless otherwise stated, all theraw starting materials, solvents and reagents were purchased fromcommercial sources (e.g., Avocado Research Chemicals, Apollo ScientificLimited, Bepharma Ltd., Combi-Blocks Inc., Sigma Aldrich Chemicals Pvt.Ltd., Ultra Labs, Toronto Research Chemicals Inc., Chemical House, RFCLLimited, Spectro Chem Pvt. Ltd., Leonid Chemicals, Loba Chemie,Changzhou Yangyuan, NeoSynth., Rankem, etc.) and used as such withoutfurther purification or reagents can be synthesized by procedures knownin the art. Typically, the progress of each reaction was monitored byTLC analysis.

Biotage Isolera® One and CombiFlash® (Teledyne Isco) Automated FlashPurification System were commonly used for the purification of crudeproducts, using the eluent combination mentioned in the respectiveprocedures. Flash Chromatography was performed using silica gel (60-100,100-200 and 230-400 mesh) from ChemLabs, with nitrogen and/or compressedair to enable pressurized eluent flow. Preparative thin-layerchromatography (preparative TLC) was carried out using silica gel (GF1500 μM 20×20 cm and GF 2000 μM 20×20 cm Prep-scored plates fromAnaltech, Inc. Delaware, USA). Analytical thin-layer chromatography(TLC) was carried out using pre-coated silica gel sheets (Merck 60F₂₅₄). Visual detection was performed with ultraviolet light,p-anisaldehyde stain, ninhydrin stain, dinitrophenyl hydrazine stain,potassium permanganate stain, or iodine. Reactions at lower temperaturewere performed by using cold baths, e.g., H₂O/ice at 0° C., andacetone/dry ice at −78° C. Reactions under microwave conditions wereconducted in a CEM Discover SP 909155 microwave oven. Melting pointswere determined by using a LabIndia MR-VIS visual melting rangeapparatus. ¹H NMR spectra were recorded at 400 MHz with a Varian V400spectrometer, Bruker 400 (unless otherwise noted) at ambienttemperature, using tetramethylsilane as internal reference. The chemicalshift values are quoted in 6 (parts per million). Mass spectra of allthe intermediates and final compounds were recorded using Acquity®UPLC-SQD (Waters) & Agilent 1290 Infinity® UHPLC with 6150 SQD machines.HPLC spectra were recorded using Agilent 1290 Infinity® UHPLC andAlliance (Waters) systems. LCMS spectra were recorded using Agilent1200® LCMS, Agilent 1290® UHPLC-SQD with diode array detector (DAD)detection LC-MS instruments using a BEH C18 column and Zorbax® HD C18column (50 mm×2.1 mm×1.7 μm) & (50 mm×2.1 mm×1.8 m), a mobile phase of0.01% of formic acid and acetonitrile or 0.01% of trifluoroacetic acidand acetonitrile, and a flow rate of 0.3 mL/min, a column temperature of70 or 50° C., and a run time of 3 to 5 min. The purity of each of thefinal compounds was determined using Waters® PDA with SQD and Agilent®DAD with 6150 SQD instruments and the following conditions:

Condition 1: Column: BEH C18 (Waters); mobile phase: 0.01% acetic acidwith acetonitrile & 0.01% acetic acid with methanol; gradient: (B/% T):0/0, 1.2/100, 2.5/100, 2.8/0, 3.0/0; flow: 0.3 mL/min; temperature: 70°C.; run time: 3.0 min.

Condition 2: Column: Zorbax® HD C18; mobile phase: 0.01% acetic acidwith acetonitrile & 0.01% acetic acid with methanol; gradient: (B/% T):0/0, 2.5/100, 4.5/100, 4.8/0, 5.0/0; flow: 0.3 mL/min; temperature: 50°C.; run time: 5.0 min

For use in the preparation of certain compounds of the invention, thefollowing intermediates were produced as follows.

Preparation 1: 2-Amino-2-(3-chlorophenyl)acetonitrile

A solution of 3-chlorobenzaldehyde (5 g, 35.0 mmol) in methanol (100 mL)was purged with ammonia gas for 2 h at RT. The mixture was cooled to 0°C., and trimethylsilylcyanide (5.293 g, 53.0 mmol) was added. Themixture was stirred at RT for 2 h. The mixture was concentrated underreduced pressure and the residue was purified by gradient columnchromatography using ethyl acetate in hexane as eluent to afford2-amino-2-(3-chlorophenyl)acetonitrile as a yellow solid (4.8 g, 81%yield). 1HNMR (400 MHz, DMSO-d₆): δ 7.57 (s, 1H), 7.47-7.40 (m, 3H),5.06 (s, 1H), 2.92 (s, 2H).

Preparation 2: 2-Amino-3-phenylpropanenitrile

To a stirred solution of 2-phenylacetaldehyde (10.0 g, 83.33 mmol) inMeOH (50 mL), was added NH₃ in MeOH (80.0 mL) and Ti(OiPr)₄ (30.7 g,108.33 mmol), and the resulting solution was stirred at RT for 2 h. Tothe reaction mixture was then added trimethylsilylcyanide (TMSCN) (14.88g, 149.9 mmol), then the reaction mixture was stirred at RT for 20 h.Reaction mixture was quenched with water, and the resulting whiteprecipitate was filtered. The filtrate was concentrated under reducedpressure, combined with ethyl acetate and washed with brine (2×15 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure, and the residue was purified by Combiflash, elutingwith MeOH in DCM, to give 2-amino-3-phenylpropanenitrile (5.4 g, 45%).1HNMR (400 MHz, DMSO-d₆): δ 7.37-7.21 (m, 5H), 3.93 (t, J=7.2 Hz, 1H),3.33-3.23 (m, 2H), 2.36 (br s, 2H). LC-MS calcd exact mass 146.08, foundm/z 147.04 [M+H]⁺.

Representative Example for Scheme 1 Example 1:(S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea(Compound #2)

Step 1: 2-Chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine

A reaction mixture of 4-nitro-1H-pyrazole (1.0 g, 8.8 mmol),2,4-dichloro-5-methylpyrimidine (1.18 g, 7.96 mmol), potassium carbonate(3.6 g, 26.4 mmol) and acetone (30 mL) was heated at 65° C. for 6 h. Thereaction mixture was evaporated; residue was suspended in water, andextracted with ethyl acetate. Organic layer was dried over sodiumsulfate, evaporated, and the residue was purified by columnchromatography over silica gel using ethyl acetate in hexanes as eluentto give 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.73 g,56%). 1HNMR (400 MHz, CDCl₃): 9.32 (s, 1H), 8.62 (s, 1H), 8.31 (s, 1H),2.69 (s, 3H). LC-MS calcd exact mass 239.02, found m/z 240.1 [M+H]⁺.

Step 2:N-(2-Chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine

A reaction mixture of2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.4 g, 1.67mmol), 2-chloroaniline (0.19 mL, 1.84 mmol), potassium carbonate (0.34g, 2.5 mmol), and dioxane (15 mL) in a glass tube was purged withnitrogen gas for 20 min. Tris(dibenzylideneacetone)dipalladium(0) (0.076g, 0.083 mmol) and BINAP (0.103 g, 0.167 mmol) were added to thereaction mixture, which was purged with nitrogen gas for another 15 min,and then the tube was sealed and heated at 90° C. for 4 hours. Reactionmixture was filtered through Celite, and the filtrate was evaporated;residue was suspended in water, and extracted with ethyl acetate.Organic layer was dried over sodium sulfate, evaporated, and the residuewas purified by column chromatography over silica gel using 20% ethylacetate in hexanes as eluent to giveN-(2-chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine(0.33 g, 60%). 11HNMR (400 MHz, DMSO-d₆): 9.23 (s, 1H), 9.17 (s, 1H),8.61 (s, 1H), 8.54 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H),7.35 (t, J=8 Hz, 1H), 7.18 (t, 1H, J=8 Hz), 2.38 (s, 3H). LC-MS calcdexact mass 330.06, found m/z 331.1 [M+H]⁺.

Step 3:4-(4-Amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine

To a solution of compoundN-(2-chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine(0.33 g, 1.0 mmol) in THF:methanol (2:1) (10 mL) which was cooled to 0°C., zinc powder (0.39 g, 6.0 mmol) and ammonium chloride (0.43 g, 8.0mmol) were added. The mixture was stirred at RT for 30 min. Reactionmixture was filtered through Celite, and filtrate was evaporated;residue was suspended in water, and extracted with DCM. Organic layerwas dried over sodium sulfate, and evaporated to give4-(4-amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine(0.24 g, 80%). This product was used in the next step without furtherpurification. 1HNMR (400 MHz, DMSO-d₆): 8.63 (s, 1H), 8.26 (s, 1H), 7.83(t, J=8 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.42 (s, 1H),7.38-7.32 (m, 1H), 7.13-7.11 (m, 1H), 4.39 (s, 2H), 2.40 (s, 3H). LC-MScalcd exact mass 300.09, found m/z 301.1 [M+H]⁺.

Step 4:(S)-1-(1-(3-Chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea

A reaction mixture of4-(4-amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine(0.15 g, 0.5 mmol), 1,1′-carbonyldiimidazole (0.32 g, 2.0 mmol), and THF(5 mL) in a CEM microwave vial was stirred at 85° C. for 20 min in CEMmicrowave. (S)-2-amino-2-(3-chlorophenyl)ethanol (0.25 g, 1.5 mmol) wasadded to the reaction mixture and was stirred at 120° C. for 20 min inCEM microwave. The reaction mixture was evaporated; residue wassuspended in water, and extracted with ethyl acetate. Organic layer wasdried over sodium sulfate, evaporated, and the residue was purified bypreparative thin layer chromatography using methanol in DCM as eluent togive(S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea(0.02 g, 8%). 1HNMR (400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 8.63 (s, 1H),8.46 (s, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 7.78 (s, 1H), 7.47 (d, J=7.6Hz, 1H), 7.35-7.26 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.79 (d, J=8 Hz,1H), 4.99-4.91 (m, 1H), 4.74-4.72 (m, 1H), 3.65-3.55 (m, 2H), 2.41 (s,3H). LC-MS m/z calcd exact mass 497.11, found m/z 498.3 [M+H]⁺; HPLCpurity 99.17%.

Representative Examples for Scheme 2 Example 2:(S)—N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-4-(5-methoxy-1H-indazol-3-yl)-1H-pyrrole-2-carboxamide(Compound #20)

Step 1: 2-Chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine

A reaction mixture of 4-nitro-1H-pyrazole (4.0 g, 35.3 mmol),2,4-dichloropyrimidine (5.23 g, 35.3 mmol), potassium carbonate (14.6 g,106 mmol) and acetone (200 mL) was heated at 65° C. for 4 h. Thereaction mixture was evaporated; residue was suspended in water, andextracted with ethyl acetate. Organic layer was dried over sodiumsulfate, evaporated, and the residue was purified by columnchromatography over silica gel using ethyl acetate in hexanes as eluentto give 2-chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (1.7 g, 21%).1HNMR (400 MHz, CDCl₃): 9.30 (s, 1H), 8.78 (d, J=5.6 Hz, 1H) 8.32 (s,1H), 7.74 (d, J=5.2 Hz, 1H).

Step 2: 1-(2-Chloropyrimidin-4-yl)-1H-pyrazol-4-amine

To a solution of 2-chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.4 g,1.77 mmol) in THF:methanol (2:1) (20 mL) which was cooled to 0° C., zincpowder (0.7 g, 10.6 mmol) and ammonium chloride (0.75 g, 14.16 mmol)were added. The mixture was stirred at RT for 30 min. Reaction mixturewas filtered through Celite, and filtrate was evaporated; residue wassuspended in water, and extracted with DCM. The organic layer was driedover sodium sulfate, and evaporated to give1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-amine (0.33 g, 97%). Thisproduct was used in the next step without further purification. 1HNMR(400 MHz, DMSO-d₆): 8.60 (d, J=5.6 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J=8Hz, 1H), 7.58 (s, 1H), 5.21 (br s, 2H). LC-MS calcd exact mass 195.03,found m/z 196.1 [M+H]⁺.

Step 3:(S)-1-(1-(3-Chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea

A mixture of 1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-amine (0.1 g, 0.51mmol), pyridine (0.041 mL, 0.51 mmol) in DCM (6 mL) was cooled to 0° C.,then 4-nitrophenyl carbonochloridate (0.102 g, 0.51 mmol) was added andthe mixture was stirred at RT for 1.5 hours. The reaction mixture wascooled to 0° C., and DIPEA (0.28 mL, 1.53 mmol) and(S)-2-amino-2-(3-chlorophenyl)ethanol (0.088 g, 0.51 mmol) were added.The reaction mixture was stirred at RT for 16 hours. The reactionmixture was diluted with DCM and washed with water and brine. Organiclayer was dried over sodium sulfate, evaporated, and the residue waspurified by column chromatography over silica gel using 60% ethylacetate in hexanes as eluent to give(S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea(0.045 g, 23%). 11HNMR (400 MHz, DMSO-d₆): 8.74 (s, 1H), 8.68 (d, J=5.6Hz, 1H), 8.45 (s, 1H), 7.92 (s, 1H), 7.80 (d, J=5.6 Hz, 1H,), 7.36-7.32(m, 2H), 7.28 (d, J=7.6 Hz, 2H), 6.96 (d, J=8 Hz, 1H), 5.00-4.98 (m,1H), 4.76-4.72 (m, 1H), 3.65-3.58 (m, 2H). LC-MS calcd exact mass392.06, found m/z 393.1 [M+H]⁺.

Step 4:(S)-1-(1-(2-(2-Chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea

A mixture of(S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea(0.02 g, 0.05 mmol), 2-chloro-4-fluoroaniline (0.009 g, 0.6 mmol),potassium carbonate (0.01 g, 0.075 mmol), and dioxane (2 mL) in a glasstube was purged with nitrogen gas for 20 min.Tris(dibenzylideneacetone)dipalladium(0) (0.002 g, 0.0025 mmol) andBINAP (0.003 g, 0.005 mmol) were added to the reaction mixture, whichwas purged with nitrogen gas for another 15 min. The tube was sealed andheated at 90° C. for 4 hours. Reaction mixture was filtered throughCelite, and filtrate was evaporated; residue was suspended in water, andextracted with ethyl acetate. Organic layer was dried over sodiumsulfate, evaporated, and the residue was purified by columnchromatography over silica gel using 60% ethyl acetate in hexanes aseluent to give(S)-1-(1-(2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea(0.003 g, 12%). 1HNMR (400 MHz, CDCl₃, plus a few drops MeOD): 8.50 (s,1H), 8.33 (d, J=5.2 Hz, 1H), 8.27-8.25 (m, 1H), 7.51 (s, 1H), 7.28-7.19(m, 1H), 7.23-7.12 (m, 3H), 7.12-7.10 (m, 1H) 7.04-6.99 (m, 1H), 6.23(d, J=6.8 Hz, 1H) 4.87-4.84 (m, 1H), 3.81-3.77 (m, 1H), 3.64-3.61 (m,1H). LC-MS calcd exact mass 501.09, found m/z 502.3 [M+H]⁺. HPLC purity98.17%.

Example 3:(S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea(Compound #55)

Step 1: 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine

To a stirred solution of 4-nitro-1H-pyrazole (4.0 g, 35.36 mmol) inacetone (100 mL) was added potassium carbonate (14.66 g, 106.1 mmol).The mixture was stirred for 15 min at RT, followed by the addition of2,4-dichloro-5-methylpyrimidine (5.76 g, 35.36 mmol), then the mixturewas stirred for 8 h at 70° C. The reaction was quenched with water (100mL), extracted with ethyl acetate (3×100 mL), followed by washing withbrine (30 mL). The combined organic layers were dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by gradient column chromatography eluting with 8% ethyl acetatein n-hexane to afford2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine, as colorlesssolid (4.2 g, 50% yield). 1HNMR (400 MHz CDCl₃): δ 9.31 (s, 1H), 8.61(s, 1H), 8.31 (s, 1H), 2.68 (s, 3H). LC-MS calcd exact mass 239.02,found m/z 240.2 [M+H]⁺.

Step 2: 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine

To a stirred solution of2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (4.2 g, 17.2mmol) in THF:methanol (50:25 mL) was added ammonium chloride (6.85 g,172.0 mmol) and zinc (5.28 g, 87.4 mmol), and then the reaction mixturewas stirred at RT for 30 min. Then the reaction mixture was filteredthrough Celite using methanol (50 mL), and the filtrate was evaporatedunder reduced pressure. It was then combined with water (100 mL), andextracted with ethyl acetate (3×100 mL), followed by brine (50 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure to give1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine as an off-whitesolid (3.0 g, 82% yield). 1HNMR (400 MHz CDCl₃): δ 8.36 (s, 1H), 8.11(s, 1H), 7.49 (d, J=8 Hz, 1H), 3.19 (s, 2H), 2.62 (s, 3H). LC-MS calcdexact mass 209.04, found m/z 210.2 [M+H]⁺.

Step 3:(S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea

To a stirred solution of1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine (0.2 g, 0.95mmol) in DCM (15 mL) was added 4-nitrophenyl carbonochloridate (0.23 g,0.11 mmol) at 0° C., and then the mixture was stirred for 2 h at RT.Then, to the mixture was added DIPEA (0.5 mL, 2.86 mmol),(S)-2-amino-2-phenylethanol (0.13 g, 0.95 mmol) in DCM (3 mL), andpyridine (0.08 mL, 0.95 mmol), and the reaction mixture was stirred atRT overnight. The reaction mixture was quenched by the addition of water(25 mL), and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure, washed with ether and then dried under highvacuum, to give(S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea,as an off-white solid (0.1 g, 28%). 1HNMR (400 MHz DMSO-d₆): δ 8.68 (s,1H), 8.61 (s, 1H), 8.52 (s, 1H), 7.89 (s, 1H), 7.3 (d, J=4.4 Hz, 4H),7.24-7.19 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 4.93 (t, J=5.2 Hz, 1H),4.75-4.71 (m, 1H), 3.65-3.55 (m, 2H), 2.48 (s, 3H). LC-MS calcd exactmass 372.11, found m/z 373.1 [M+H]⁺.

Step 4:(S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea

To a stirred solution of(S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea(0.1 g, 0.26 mmol) in dioxane (5 mL) was added potassium carbonate(0.055 g, 0.40 mmol), benzo[d][1,3]dioxol-5-amine (0.044 g, 0.32 mmol),and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.016 g, 0.026 mmol).Then the mixture was degassed with argon gas for 20 min, followed by theaddition of tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013mmol), and then the mixture was stirred for 4 h at 100° C. in sealedglass tube. The reaction mixture was filtered through Celite bed, andthe filtrate was quenched with water (15 mL), and extracted with ethylacetate (3×20 mL). The combined organic layers were dried over sodiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by gradient column chromatography eluting with 3.5% methanol inDCM, to afford(S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea,as an off-white solid (4 mg, 4%). 1HNMR (400 MHz, DMSO-d₆): δ 9.44 (s,1H), 8.81 (s, 1H), 8.56 (s, 1H), 8.34 (d, J=12.4 Hz, 1H), 7.77 (s, 1H),7.37 (d, J=1.6 Hz, 1H), 7.31-7.29 (m, 4H), 7.23-7.19 (m, 1H) 7.12-7.09(m, 1H), 6.9 (d, J=7.6 Hz, 1H), 6.8 (d, J=8 Hz, 1H), 5.97 (s, 2H), 4.95(s, 1H), 4.74-4.69 (m, 1H), 3.63-3.55 (m, 2H), 2.45 (s, 3H). LC-MS calcdexact mass 473.18, found m/z 474.5 [M+H]⁺; HPLC Purity 98.33%, ChiralHPLC Purity 99.01%, mp 208.3° C.

Representative Example for General Scheme 3 Example 4:(S)-1-(2-((2-Chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide(Compound #29)

Step 1: Methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

To a solution of methyl 1H-pyrrole-3-carboxylate (3.0 g, 24 mmol) inacetonitrile (100 mL) were added 2,4-dichloro-5-methylpyrimidine (5.9 g,36 mmol) and potassium carbonate (6.6 g, 48 mmol). The reaction wasstirred at reflux for 12 h. The reaction mixture was diluted with ethylacetate (500 mL) and then washed with water and brine. The ethyl acetatelayer was dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by gradient columnchromatography using ethyl acetate in hexane as eluent to afford methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate as anoff-white solid (3.2 g, 53%). ¹HNMR (400 MHz, CDCl₃): δ 8.51 (s, 1H),8.0 (s, 1H), 7.41 (d, J=2.4 Hz, 1H,), 6.79 (t, J=1.2 Hz, 1H,), 3.85 (s,3H), 2.51 (s, 3H). LC-MS calcd exact mass 251.05, found m/z 252.2[M+H]⁺.

Step 2: Methyl1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

To a solution of methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (0.3 g,0.1195 mmol) in dioxane (10 mL) were added 2-chloro-4-fluoroaniline(0.17 g, 0.1195 mmol) and potassium carbonate (0.24 g, 1.17 mmol). Theresulting reaction mixture was purged with nitrogen gas for min, then2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(0.074 g, 0.119 mmol) andpalladium(dibenzylidineacetone)dipalladium(0) (0.054 g, 0.059 mmol) wereadded. The reaction mixture was stirred at 100° C. for 12 h. Thereaction mixture was diluted with ethyl acetate (200 mL) and filteredthrough Celite bed. The bed was washed with ethyl acetate (2×50 mL). Thefiltrate was washed several times with cold water and then with brine.The organic layer was dried over sodium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by gradient columnchromatography using ethyl acetate in hexane as eluent to afford methyl1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylateas an off-white solid (0.25 g, 58%). ¹HNMR (400 MHz, CDCl₃): δ 8.40-8.36(m, 2H), 7.95 (s, 1H), 7.51 (s, 1H), 7.40-7.34 (m, 1H), 7.19-7.16 (m,1H), 7.07-6.99 (m, 1H), 6.77-6.76 (m, 1H), 3.86 (s, 3H), 2.40 (s, 3H).LC-MS calcd exact mass 360.08, found m/z 361.3 [M+H]⁺.

Step 3:1-(2-((2-Chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylicacid

To a solution of methyl1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate(0.25 g, 0.833 mmol) in methanol (20.0 mL) was added 2N-sodium hydroxidesolution (10 mL). The reaction mixture was stirred at 50° C. for 2 h.Methanol was removed under reduced pressure and the pH was adjusted topH-6.5-7 by addition of dilute hydrochloric acid. The aqueous layer wasextracted with ethyl acetate (3×50 mL) and the combined organic layerwas dried over sodium sulfate, filtered, and evaporated under reducedpressure to afford1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylicacid as an off-white solid (0.17 g, 71%). ¹HNMR (400 MHz, DMSO-d₆): δ12.14 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.67-7.64 (m,1H), 7.50-7.48 (m, 1H), 7.36 (t, J=2.8 Hz, 1H), 7.24-7.19 (m, 1H), 6.57(t, J=2.0 Hz, 2H), 2.27 (s, 3H). LC-MS calcd exact mass 346.06, foundm/z 347.3 [M+H]⁺.

Step 4:(S)-1-(2-((2-Chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide

To a solution of1-(2-(2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylicacid (0.05 g, 0.144 mmol) in NMP (2.0 mL) were added(S)-2-amino-2-(3-chlorophenyl)ethanol (0.029 g, 0.173 mmol), EDC (0.055g, 0.288 mmol) and HOBt (0.005 g, 0.043 mmol). To the resulting reactionmixture was added triethylamine (0.04 g, 0.432 mmol) dropwise at RT. Thereaction mixture was stirred at RT for 15 h. The reaction mixture waspoured into cold water (10 mL) and then extracted with ethyl acetate(3×50 mL). The combined organic layer was dried over sodium sulfate,filtered and evaporated under reduced pressure. The residue wasdissolved in a small volume of DCM and then diluted with ether. Thesolvent was decanted. The solid that had formed was washed with etherand n-pentane to afford(S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamideas an off-white solid (0.022 g, 31%). 1HNMR (400 MHz, DMSO-d₆): δ 8.99(s, 1H), 8.37 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.69-7.65(m, 1H), 7.49-7.41 (m, 1H), 7.37-7.18 (m, 6H), 6.75 (s, 1H), 5.04-4.99(m, 1H), 4.92 (br s, 1H), 3.65-3.64 (m, 2H), 2.28 (s, 3H). LC-MS calcdexact mass 499.10, found m/z 500.3 [M+H]⁺; HPLC Purity: 99.03%, chiralHPLC: 99.66%.

Example 5:(S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide(Compound #39)

Step 1: Methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate

To a stirred solution of methyl-1H-pyrazole-4-carboxylate (1.00 g, 6.134mmol) in acetonitrile (20 mL) was added potassium carbonate (2.543 g,18.40 mmol), and the mixture was stirred for 5 min at RT. To thismixture was added 2,4-dichloro-5-methylpyrimidine (0.773 g, 6.134 mmol),and the mixture was stirred at 80° C. overnight. The mixture was cooledand water (15 mL) was added, and the mixture was extracted with ethylacetate (3×50 mL). The combined organic layer was dried over sodiumsulfate, then evaporated under reduced pressure and the residue waspurified by gradient column chromatography using ethyl acetate inn-hexane as eluent to give methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate as acolorless solid (0.65 g, 42%). 1HNMR (400 MHz, CDCl₃): δ 9.08 (s, 1H),8.54 (s, 1H), 8.15 (s, 1H), 3.89 (s, 3H), 2.67 (s, 3H).

Step 2: Methyl1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate

To a solution ofmethyl-1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate(0.3 g, 1.18 mmol) in isopropanol (7 mL) was added DIPEA (0.43 mL, 2.47mmol) and cyclopropylamine (0.09 mL, 1.3 mmol). The reaction mixture wasstirred in a sealed glass tube at 85° C. overnight. The reaction mixturewas cooled and quenched with water (10 mL), and extracted with ethylacetate (3×10 mL). The organic layer was dried over sodium sulfate,filtered and evaporated under reduced pressure, and the residue waspurified by gradient column chromatography using ethyl acetate inn-hexane as eluent to afford methyl1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylateas a colorless solid (0.17 g, 52%). 11HNMR (400 MHz, CDCl₃): δ 8.97 (s,1H), 8.27 (s, 1H), 8.09 (s, 1H), 5.26 (s, 1H), 3.87 (s, 3H), 2.80-2.76(m, 1H), 2.47 (s, 3H), 0.87-0.83 (m, 2H), 0.56 (t, J=7.2 Hz, 2H). LC-MScalcd exact mass 273.12, found m/z 274.6 [M+H]⁺.

Step 3:1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylicacid

To a stirred solution of methyl1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate(0.2 g, 0.72 mmol) in THF (7 mL) and water (1 mL) was added lithiumhydroxide monohydrate (0.306 g, 7.29 mmol). The reaction mixture wasstirred at 50° C. for 4 h. The mixture was cooled and concentrated underreduced pressure, and neutralized (pH˜7) by addition of 1N HCl. Thesolid that formed was filtered to give1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylicacid as a colorless solid (0.122 g, 65%). 1HNMR (400 MHz, DMSO-d₆): δ12.0 (br s, 1H), 8.82 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.48 (s, 1H),2.74-2.71 (m, 1H), 2.30 (s, 3H), 0.69-0.65 (m, 2H), 0.48-0.44 (m, 2H).LC-MS calcd exact mass 259.11, found m/z 260.2 [M+H]⁺.

Step 4:(S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide

To a stirred solution of1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylicacid (0.035 g, 0.134 mmol) in NMP (0.8 mL) was added EDC (0.051 g, 0.26mmol), HOBt (0.005 g, 0.04 mmol), and triethylamine (0.05 mL, 0.4 mmol),and the mixture was then stirred at RT for 10 min. To this mixture wasadded (S)-2-amino-2-(3-chlorophenyl)ethanol (0.027 g, 0.16 mmol). Thereaction mixture was stirred at RT overnight. The mixture was dilutedwith water (10 mL) and extracted with ethyl acetate (2×20 mL). Combinedorganic layers were washed with brine, dried over sodium sulfate, andevaporated under reduced pressure. The residue was purified by columnchromatography using methanol in DCM as eluent to afford(S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamideas a colorless solid (0.011 g, 20%). 1HNMR (400 MHz, DMSO-d₆): δ 9.00(s, 1H), 8.61 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.44 (d,J=11.2 Hz, 2H), 7.36-7.27 (m, 3H), 5.07-5.01 (m, 1H), 4.98-4.95 (m, 1H),3.66-3.65 (m, 2H), 2.76-2.73 (m, 1H), 2.34 (s, 3H), 0.68 (d, J=5.2 Hz,2H), 0.48 (d, J=2.4 Hz, 2H). LC-MS calcd exact mass 412.14, found m/z413.2 [M+H]⁺; HPLC Purity 99.32%, Chiral HPLC Purity 99.76%.

Representative Example for General Scheme 4 Example 6:N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide(Compound #136)

Step 1: Methyl 1H-pyrrole-3-carboxylate

To a solution of 1H-pyrrole-3-carboxylic acid (4.3 g, 38.7 mmol) inmethanol (40 mL) that was cooled to 0-5° C. was added 6N HCl (9 mL). Themixture was stirred at RT for 5 min, and then heated at refluxovernight. The reaction mixture was cooled and concentrated underreduced pressure, then cooled to 0° C. and adjusted to pH ˜7 by theaddition of saturated sodium bicarbonate. The mixture was extracted withethyl acetate, and the organic layer was dried over sodium sulfate,filtered and evaporated under reduced pressure to afford methyl1H-pyrrole-3-carboxylate as a brown solid (4 g, 83%). ¹HNMR (400 MHz,CDCl₃): δ 8.56 (br s, 1H), 7.43 (s, 1H), 6.75 (s, 1H), 6.65 (s, 1H),3.92 (s, 3H). LC-MS calcd exact mass 125.05, found m/z 126.2 [M+H]⁺.

Step 2: Methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

To a solution of methyl-1H-pyrrole-3-carboxylate (1.4 g, 11.2 mmol) inacetonitrile (50 mL) was added potassium carbonate (3.09 g, 22.4 mmol).The mixture was stirred at RT for 15 min and then2,4-dichloro-5-methylpyrimidine (2.738 g, 16.8 mmol) was added. Theresulting mixture was heated at reflux overnight. The reaction mixturewas cooled and then evaporated under reduced pressure, combined withwater and extracted with ethyl acetate. The combined organic layer wasdried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was purified by gradient column chromatographyusing ethyl acetate in n-hexane as eluent to afford methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate as a whitesolid (1.2 g, 43%). ¹HNMR (400 MHz, CDCl₃): δ 8.50 (s, 1H), 7.99 (s,1H), 7.40-7.39 (m, 1H), 6.78-6.77 (m, 1H), 3.85 (s, 3H), 2.51 (s, 3H).LC-MS calcd exact mass 251.05, found m/z 252.3 [M+H]⁺.

Step 3: Methyl1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

To a solution ofmethyl-1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (3.1g 12.31 mmol) in dioxane (20 mL) was added potassium carbonate (2.549 g,18.47 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.766 g,1.231 mmol) and 2,2-difluorobenzo[d][1,3]dioxol-5-amine (2.23 g, 12.92mmol). The reaction mixture was degassed with argon for 15 min, followedby the addition of tris(dibenzylideneacetone)-dipalladium(0) (0.563 g,0.615 mmol). The resulting mixture was stirred in a sealed glass tube at100° C. for 9 h. The reaction mixture was filtered on Celite, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in water, extracted with ethyl acetate, and the combinedorganic phase was washed with water and brine. The combined organicphase was dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by gradient columnchromatography using ethyl acetate in n-hexane as eluent to affordmethyl1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylateas an off-white solid (2.3 g, 48%). ¹HNMR (400 MHz, CDCl₃): δ 8.34 (s,1H), 7.95 (s, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.34 (t, J=2.8 Hz, 1H), 7.23(s, merged with CDCl₃ peak, 1H), 7.06-6.99 (m, 2H), 6.78-6.77 (m, 1H),3.86 (s, 3H), 2.40 (s, 3H). LC-MS calcd exact mass 388.10, found m/z389.3 [M+H]⁺.

Step 4:1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylicacid

To a solution of methyl1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate(1.0 g, 2.5 mmol) in THF (40 mL) and water (20 mL) was added lithiumhydroxide monohydrate (0.648 g, 15.4 mmol). The resulting mixture washeated to reflux at 70° C. for 12 h. The reaction mixture was cooled andthen concentrated under reduced pressure, and adjusted to pH ˜6 by theaddition of 1N HCl. The solid was filtered and washed with n-pentane anddiethyl ether to afford1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylicacid as a white solid (0.85 g, 88%). ¹HNMR (400 MHz, DMSO-d₆): δ 11.98(br s, 1H), 9.58 (s, 1H), 8.38 (s, 1H), 7.94-7.82 (m, 2H), 7.36 (d, 2HJ=8 Hz), 7.0 (d, 1H J=8.4 Hz), 6.69 (s, 1H), 2.38 (s, 3H). LC-MS calcdexact mass 374.08, found m/z 375.1 [M+H]⁺.

Step 5:N-((3-Chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide

To a solution of1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylicacid (0.2 g, 0.53 mmol) in DCM (15 mL) and THF (3 mL) was addedtriethylamine (0.2 mL, 1.6 mmol), and the mixture was stirred for 5 minunder nitrogen atmosphere. Then, to the mixture was added2-amino-2-(3-chlorophenyl)acetonitrile (0.1 g, 0.64 mmol), EDC (0.2 g,1.06 mmol), and HOBt (0.021 g, 0.16 mmol). The resulting mixture wasstirred at RT overnight. The reaction mixture was quenched with water,and extracted with DCM. The combined organic layer was washed with waterand brine, dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by gradient columnchromatography using ethyl acetate in n-hexane as eluent to affordN-((3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamideas a white solid (0.1 g, 36%). 1HNMR (400 MHz, CDCl₃): δ 8.35 (s, 1H),7.95 (s, 1H), 7.6 (s, 1H), 7.56 (s, 1H), 7.4 (d, J 6.8 Hz, 1H),7.41-7.38 (m, 3H), 7.0-6.99 (m, 2H), 6.6 (s, 1H), 6.4 (d, J 8.8 Hz, 2H),6.34 (d, J 8.8 Hz, 2H), 2.4 (s, 3H). LC-MS calcd exact mass 522.10,found m/z 523.2 [M+H]⁺, HPLC purity 98.03%.

Step 6:N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[I][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide

To a solution ofN-(3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide(0.1 g, 0.191 mmol) in methanol (10 mL) was added methanolic ammonia (20mL) at 0° C., followed by the addition of Raney nickel (0.05 g). Theresulting reaction mixture was stirred overnight at RT under a hydrogenatmosphere using a bladder. The reaction mixture was filtered on Celite,and the filtrate was evaporated under reduced pressure. The residue waspurified by gradient column chromatography using methanol in DCM aseluent to affordN-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamideas an off-white solid (0.03 g, 30%). 1HNMR (400 MHz, CDCl3): δ 8.34 (s,1H), 7.95 (s, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.34 (t, J=2.8 Hz, 1H), 7.23(s, merged with CDCl3 peak, 1H), 7.06-6.99 (m, 2H), 6.78-6.77 (m, 1H),3.86 (s, 3H), 2.40 (s, 3H). LC-MS calcd exact mass 526.13, found m/z527.5 [M+H]⁺.

Example 7:N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #225)

Step 1: Methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

To a solution of methyl-1H-imidazole-4-carboxylate (10.37 g, 74.0 mmol)in acetonitrile (200 mL) was added 2,4-dichloro-5-methylpyrimidine (10g, 61.7 mmol) and potassium carbonate (25.5 g, 185.2 mmol), and then themixture was stirred at RT for 16 h under an inert atmosphere. Thereaction mixture was quenched with water, and extracted with ethylacetate. The organic layer was washed with water, dried over sodiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by gradient column chromatography using ethyl acetate in hexaneas eluent to afford methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate as awhite solid (11 g, 75%). 1HNMR (400 MHz, DMSO-d₆): δ 8.88 (s, 1H), 8.38(s, 2H), 3.80 (s, 3H), 2.41 (s, 3H). LC-MS exact mass calcd 252.04,found m/z 253.2 [M+H]⁺.

Step 2: Methyl1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate

To a solution of1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (5 g,19.7 mmol) in isopropanol (30 mL) was added DIPEA (7.658 g, 59.0 mmol)and tetrahydro-2H-pyran-4-amine (2.402 g, 23.0 mmol). The resultingmixture was stirred in a sealed glass tube at 100° C. for 17 h. Thereaction mixture was cooled to RT, and allowed to form crystals. Thecrystals were filtered, washed with hexane, and dried under vacuum toafford methyl1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxylateas an off-white solid (5.2 g, 83%). 1HNMR (400 MHz, DMSO-d₆): δ 8.36 (s,1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.39 (d, J=7.6 Hz, 1H), 3.90-3.83 (m,3H), 3.78 (s, 3H), 3.37 (t, J=11.6 Hz, 2H), 2.16 (s, 3H), 1.82 (d, J 12Hz, 2H), 1.54-1.45 (m, 2H), LC-MS exact mass calcd 317.15, found m/z318.2 [M+H]⁺.

Step 3:N-((3-Chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a solution of methyl1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate(0.500 g, 1.57 mmol) in toluene (20 mL) was added2-amino-2-(3-chlorophenyl)acetonitrile (0.392 g, 2.3 mmol) andtrimethylaluminium (2M solution in toluene; 1.96 mL, 2.5 eq). Theresulting mixture was stirred in CEM microwave at 100° C. for 1 h. Thereaction mixture was quenched with water, and extracted with ethylacetate. The organic layer was washed with cold water, dried over sodiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by gradient column chromatography twice using methanol in DCMas eluent to giveN-((3-chloro-phenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamideas a yellow solid (0.29 g). LC-MS exact mass calcd 451.15, found m/z452.2 [M+H]⁺.

Step 4:N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a solution ofN-((3-chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(0.700 g, 1.54 mmol) in methanol (15 mL) was added nickel dichloridehexahydrate (0.552 g, 2.3 mmol) at 0° C. under an inert atmosphere, andthen the mixture was stirred to obtain a clear solution. To the reactionmixture was slowly added sodium borohydride (0.175 g, 4.6 mmol) at 0° C.and then the mixture was stirred for 10 min at 0° C. The reactionmixture was filtered through Celite and the filtrate was evaporatedunder reduced pressure. The residue was purified by gradient columnchromatography using methanol in dichloromethane as eluent to affordN-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(racemic mixture) as an off-white solid (0.050 g, 7%), which was useddirectly in the chiral HPLC separation. Data obtained for a separatebatch that was prepared in a similar manner: 1HNMR (400 MHz, DMSO-d6): δ8.53 (d, J=8 Hz 1H), 8.32 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.40 (s,1H), 7.32-7.27 (m, 4H), 4.98-4.88 (m, 1H), 3.83-3.81 (m, 3H), 3.37-3.35(m, 2H), 2.95-2.88 (m, 2H), 2.16 (s, 3H), 1.79 (d, J=11.2 Hz, 2H),1.50-1.40 (m, 2H). LC-MS exact mass calcd 455.18, found m/z 456.5[M+H]⁺.

Example 8a: Enantiomer #1,(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;and Example 8b: Enantiomer,(R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #225a and Compound #225b, respectively)

RacemicN-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)-amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(50 mg) was dissolved in 1 mL 50:50 methanol/DCM, and subjected tochiral HPLC purification using Chiralpak® IA column [250 mm×4.6 mm×5μm], with mobile phase as isopropyl alcohol with 0.01% diethylamine(100%); flow rate 1 mL/min. Eluted fractions of the two enantiomers wereseparately collected and these fractions were separately evaporated toafford 12 mg (48% recovery) of Enantiomer #1 ((S), Compound #225a) asthe first eluting enantiomer, and 10 mg (40% recovery) of Enantiomer #2((R), Compound #225b) as the second eluting enantiomer, with >98.1% eeand >98.7% ee, respectively.

Example 8a, Compound #225a (Enantiomer #1,(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide):1HNMR (400 MHz, DMSO-d₆): δ 8.58 (d, J=6.8 Hz, 1H), 8.33 (s, 1H), 8.27(s, 1H), 8.07 (s, 1H), 7.41 (s, 1H), 7.36-7.28 (m, 4H), 4.97 (br s, 1H),3.84-3.82 (m, 3H), 3.38-3.33 (m, 2H), 3.01-2.94 (m, 2H), 2.16 (s, 3H),1.80 (d, J=11.6 Hz, 2H), 1.52-1.44 (m, 2H). LC-MS exact mass calcd455.18, found m/z 456.2 [M+H]⁺.

Example 8b, Compound #225b (Enantiomer #2,(R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide):1HNMR (400 MHz, DMSO-d₆): δ 8.58 (d, J=8 Hz, 1H), 8.33 (s, 1H), 8.27 (s,1H), 8.07 (s, 1H), 7.42 (s, 1H), 7.36-7.27 (m, 4H), 5.02-4.91 (m, 1H),3.84-3.82 (m, 3H), 3.35 (m, 2H), 3.05-2.91 (m, 2H), 2.16 (s, 3H), 1.79(d, J=11.6 Hz, 2H), 1.51-1.4 (m, 2H). LC-MS exact mass calcd 455.18,found m/z 456.2 [M+H]⁺.

Representative Example for General Scheme 5 Example 9:1-(2-((4-Fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide(Compound #153)

Step 1:1-(2-Chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carbaldehyde

A mixture of 2,4-dichloro-5-methylpyrimidine (2.50 g, 15.33 mmol),2-methyl-1H-imidazole-4-carbaldehyde (1.85 g, 16.87 mmol), and potassiumcarbonate (4.65 g, 33.74 mmol) in DMF (30 mL) was stirred at RT for 18h. The mixture was diluted with water (100 mL) and extracted with ethylacetate (3×100 mL). The organic layer was dried over sodium sulfate andevaporated under reduced pressure, and the residue was purified bycolumn chromatography over silica gel (100-200 mesh) using 80-90% ethylacetate in hexanes as eluent to obtain1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carbaldehyde(0.5 g, 15%). 1HNMR (400 MHz, DMSO-d₆): δ 9.76 (s, 1H), 8.99 (s, 1H),8.40 (s, 1H), 2.35 (s, 1H), 2.22 (s, 3H). LC-MS: exact mass calcd236.05, found m/z 237.07 [M+H]⁺, purity: 99.23%.

Step 2:1-(2-Chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carboxylicacid

To a solution of1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carbaldehyde(0.5 g, 2.11 mmol) in t-butanol (1.5 mL) and THF (7 mL) at RT was added2-methyl-2-butene. To this mixture, a solution of sodium chlorite (1.87g, 20.7 mmol) and sodium dihydrogenphosphate (1.5 g, 12.28 mmol) inwater (5 mL) was added slowly. After TLC showed complete reaction, themixture was diluted with water (25 mL) and washed with ethyl acetate(2×10 mL). The aqueous layer was concentrated under vacuum and extractedwith 10% methanol in DCM (3×50 mL). The organic layer was concentratedunder reduced pressure to obtain1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carboxylicacid (0.70 g) as a white solid. LC-MS exact mass calcd 252.04, found m/z253.0 [M+H]⁺.

Step 3:1-(2-Chloro-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide

To a solution of1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carboxylicacid (0.5 g, 1.98 mmol) and triethylamine (0.5 mL, 3.96 mmol) in DCM wasadded slowly (DL)-2-amino-2-phenylethan-1-ol (0.288 g, 2.18 mmol). Tothis mixture, T3P (2.5 mL, 3.96 mmol, 50% solution in ethyl acetate) wasadded and the mixture was stirred at RT for 18 h. After TLC showedreaction was complete, the mixture was quenched by the addition of water(30 mL). The mixture was extracted with DCM (3×30 mL), and the organiclayer was washed with brine, dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (230-400 mesh) using 5% MeOH in DCM as eluent to obtain1-(2-chloro-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide(0.580 g, 79%) as an off-white solid. 1HNMR (400 MHz, DMSO-d₆): δ 8.95(s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.36-7.35 (m, 2H),7.33-7.34 (m, 3H), 7.22-7.21 (m, 1H), 5.02-4.98 (m, 2H), 3.74-3.69 (m,2H), 2.36 (s, 3H), 2.21 (s, 3H). LC-MS Exact mass calcd 371.11, foundm/z 372.0 [M+H]⁺.

Step 4:1-(2-((4-Fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide

A mixture of1-(2-chloro-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide(0.5 g, 1.42 mmol), 4-fluoroaniline (0.173 g, 1.56 mmol), and potassiumcarbonate (0.39 g, 2.84 mmol) in dioxane (20 mL) in a glass tube waspurged with argon gas for 10 min.Tris(dibenzylideneacetone)dipalladium(0) (0.130 g, 0.142 mmol) and BINAP(0.0.089 g, 0.142 mmol) were added to the reaction mixture which waspurged with argon gas for another 10 min. The mixture was heated at 90°C. in a sealed glass tube for 6 hours. After reaction was complete, thereaction mixture was cooled, diluted with water and extracted with ethylacetate (3×100 mL). The organic layer was dried over sodium sulfate andevaporated, and the residue was purified by flash column chromatographyover silica gel (230-400 mesh) using 80% ethyl acetate in hexanes aseluent to give1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide(0.109 g, 17%) as a white solid. 1HNMR (400 MHz, DMSO-d₆): δ 9.89 (s,1H), 8.60 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.70-7.67 (m,2H), 7.37 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.2 Hz, 2H), 7.24 (d, J=7.2 Hz,1H), 7.16 (t, J=8.8 Hz, 2H), 5.02 (d, J=4.8 Hz, 2H), 3.77-3.69 (m, 2H),2.35 (s, 3H), 2.03 (s, 3H). LC-MS calcd exact mass 446.19, found m/z447.52 [M+H]⁺, purity: 96.12%.

Representative Examples for General Scheme 6 Example 10:N—((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #192)

Step 1: Methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

To a stirred solution of methyl-1H-imidazole-4-carboxylate (7 g, 42.9mmol) in acetonitrile (50 mL), was added potassium carbonate (11.87 g,85.88 mmol). The mixture was stirred at RT and then2,4-dichloro-5-methylpyrimidine (5.41 g, 42.9 mmol) was added, and themixture was stirred at RT overnight. The mixture was combined with water(50 mL) and extracted with ethyl acetate (3×150 mL). The combinedorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure and the residuewas purified by gradient column chromatography using ethyl acetate inn-hexane as eluent to afford methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate as awhite solid (4.5 g, 41%). 1HNMR (400 MHz, DMSO-d₆): δ 8.88 (s, 1H), 8.38(s, 1H), 3.8 (s, 3H), 2.41 (s, 3H). LC-MS calcd exact mass 252.04, foundm/z 253.2 [M+H]⁺.

Step 2: (S)-Methyl1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate

To a solution of methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.6 g,2.37 mmol) in isopropanol (30 mL) was added (S)-tetrahydrofuran-3-amine(0.310 g, 3.56 mmol) and DIPEA (1.53 g, 11.8 mmol), and the mixture wasstirred in a sealed glass tube for 36 h at 100° C. The mixture wascooled and then concentrated under reduced pressure, diluted with water(50 mL) and extracted with ethyl acetate (2×100 mL). The organic layerwas washed with brine (5 mL), dried over anhydrous sodium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby gradient column chromatography using ethyl acetate in hexane aseluent to afford (S)-methyl1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylateas a white solid (0.45 g, 63% yield). 1HNMR (400 MHz, CDCl₃): δ 8.28 (s,1H), 8.16 (d, J=2.4 Hz, 2H,), 5.47 (s, 1H), 4.56 (s, 1H), 4.0-3.88 (m,5H), 3.87-3.85 (m, 1H), 3.75-3.71 (m, 1H), 2.31 (s, 3H), 2.36-2.33 (m,1H), 1.92-1.85 (m, 2H), LC-MS calcd exact mass 303.13, found m/z 304.4[M+H]⁺.

Step 3:N—((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of(S)-methyl-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate(0.45 g, 1.48 mmol) in toluene (25 mL) was added(S)-2-amino-2-(3-chlorophenyl)ethanol (0.509 g, 2.96 mmol) andtrimethylaluminum (2M solution in toluene; 2.2 mL, 4.45 mmol) at 0° C.in CEM microwave vial. The vial was sealed and the reaction mixture wasstirred at 100° C. for 2 h in CEM microwave. The mixture was cooled,quenched with water and extracted with ethyl acetate (3×200 mL). Thecombined organic layer was washed with brine (10 mL), dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. The residue was purified by gradient column chromatographyusing methanol in DCM as eluent to affordN—(S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamideas a white solid (0.23 g, 35%). 1HNMR (400 MHz, DMSO-d₆): δ 8.38 (t,J=8.4 Hz, 2H) 8.29 (s, 1H), 8.11 (s, 1H), 7.60 (d, J=5.2 Hz, 1H), 7.43(s, 1H), 7.31 (d, J=15.6 Hz, 3H), 5.02 (d, J=5.2 Hz, 2H), 4.34 (s, 1H),3.87-3.78 (m, 2H), 3.72-3.67 (m, 3H), 3.55-3.28 (m, 1H), 2.19 (s, 3H),2.19-2.08 (m, 1H), 1.89-1.85 (m, 1H). LC-MS calcd exact mass 442.15,found m/z 443.5 [M+H]⁺. HPLC Purity 99.2%, chiral HPLC Purity 99.7%; mp117° C.

Example 11:N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #201)

Step 1: Methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

To a stirred solution of methyl 1H-imidazole-4-carboxylate (2.32 g, 18.4mmol) in acetonitrile (75 mL) was added potassium carbonate (5.08 g,36.8 mmol). The reaction mixture was stirred at RT for 5 min, then2,4-dichloro-5-methylpyrimidine (2 g, 18.4 mmol) was added. Theresulting mixture was stirred at RT overnight. The mixture was quenchedwith water (50 mL) and extracted with ethyl acetate (3×150 mL). Thecombined organic layer was dried over sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by gradientcolumn chromatography using ethyl acetate in n-hexane as eluent toafford methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate as anoff-white solid (53.7%)._¹HNMR (400 MHz, CDCl₃): δ 8.63 (s, 1H), 8.25(d, J=5.2 Hz, 2H), 3.95 (s, 3H), 2.52 (s, 3H). LC-MS calcd exact mass252.04, found m/z 253.1 [M+H]⁺.

Step 2: Methyl1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate

To a solution of1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.27 g,1.07 mmol) in isopropanol (5 mL) was added DIPEA (0.58 mL, 3.21 mmol)and tetrahydro-2H-pyran-4-amine (0.16 mL, 1.60 mmol). The resultingmixture was stirred in a sealed glass tube at 100° C. for 20 h. Thereaction mixture was quenched with water (10 mL), and extracted withethyl acetate (50 mL). The organic layer was dried over sodium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby gradient column chromatography using methanol in DCM as eluent toafford methyl1-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylateas an off-white solid (0.25 g, 76%). 11HNMR (400 MHz, DMSO-d₆): δ 8.35(s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 7.38 (d, J=7.6 Hz, 1H), 3.85-3.82(m, 3H), 3.77 (s, 3H), 3.37 (t, J=10 Hz, 2H), 2.15 (s, 3H), 1.80 (d,J=10.4 Hz, 2H), 1.50-1.46 (m, 2H). LC-MS calcd exact mass 317.15, foundm/z 318.4 [M+H]⁺.

Step 3:N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a solution ofmethyl-1-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate(0.1 g, 0.315 mmol) in toluene (10 mL) was added2-amino-2-(3-chlorophenyl)ethanol (0.10 g, 0.63 mmol) andtrimethylaluminum (2M solution in toluene; 0.78 mL, 1.57 mmol). Theresulting mixture was stirred in CEM microwave at 100° C. for 1.5 h. Themixture was cooled, and then quenched with water (10 mL) and extractedwith ethyl acetate (50 mL). The organic layer was washed with water (10mL), dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was purified by gradient column chromatographyusing methanol in DCM as eluent to affordN-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamideas an off-white solid (0.12 g, 86%). 1HNMR (400 MHz, DMSO-d₆): δ 8.41(d, J=7.8 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.42 (s,1H), 7.38 (d, J=9.6 Hz, 1H), 7.32-7.27 (m, 3H), 5.05-4.98 (m, 2H),3.85-3.77 (m, 3H), 3.71 (t, J=4 Hz, 2H), 3.38 (t, J=8 Hz, 2H), 2.16 (s,3H), 1.80 (d, J=11.2 Hz, 2H), 1.51-1.44 (m, 2H). LC-MS calcd exact mass456.17, found m/z 457.5 [M+H]⁺; HPLC purity 99.53%.

Example 12:(S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #211)

Step 1 and Step 2: The Procedure Followed was Similar to that Describedin Example 11 Step 3:(S)—N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a solution of methyl1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate(0.07 g, 0.22 mmol) in toluene (2 mL) was added(S)-2-amino-2-(3-chlorophenyl)ethanol (0.075 g, 0.44 mmol) andtrimethylaluminum (2M solution in toluene; 0.22 mL, 0.44 mmol). Theresulting mixture was stirred in CEM microwave at 100° C. for 1.5 h. Themixture was cooled, quenched with water (10 mL), and extracted withethyl acetate (50 mL). The organic layer was washed with water (10 mL),dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was purified by gradient column chromatographyusing methanol in DCM as eluent and the isolated product was then washedwith n-pentane to afford(S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamideas an off-white solid (0.060 g, 60%). 1HNMR (400 MHz, DMSO-d₆): δ 8.39(d, J=8 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.43 (s, 1H),7.37-7.32 (m, 3H), 7.29 (br s, 1H), 5.02 (d, J=8 Hz, 2H), 3.85-3.82 (m,3H), 3.72 (t, J=8 Hz, 2H), 3.39-3.26 (m, 2H), 2.17 (s, 3H), 1.81 (d, J=8Hz, 2H), 1.48 (d, J=8 Hz, 2H). LC-MS calcd exact mass 456.17, found m/z457.2 [M+H]⁺; HPLC purity 99.81%, Chiral HPLC purity 99.92%; mp 145° C.

Representative Example for a Combination of Methods Used in Schemes 4and 3 Example 13: N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl) amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #93)

Step 1 and Step 2: The Procedure Followed was Similar to that Describedin Example 11 Step 3:1-(5-Methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid

To a stirred solution of methyl1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate(1.5 g, 4.731 mmol) in tetrahydrofuran (30 mL) was added potassiumtrimethylsilanolate (1.82 g, 14.18 mmol) at 0° C. The reaction mixturewas stirred at 45° C. for 1.5 h. Then the reaction mixture was quenchedwith water (25 mL), and washed with ethyl acetate (2×10 mL). The aqueouslayer was adjusted to pH ˜5-6 by addition of 4N HCl solution. Theaqueous layer was then extracted with ethyl acetate (3×60 mL), and thecombined organic layer was concentrated under reduced pressure, toafford1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid, as an off-white solid, (1.2 g, 84%). ¹HNMR (400 MHz, DMSO-d₆): δ12.47 (br s, 1H), 8.33 (s, 1H), 8.23 (br s, 1H), 8.20 (s, 1H), 7.36 (d,J=7.6 Hz, 1H), 3.88 (br s, 1H), 3.83 (d, J=11.6 Hz, 2H), 3.36 (t, J=10.8Hz, 2H), 2.15 (s, 3H), 1.80 (d, J=10.4 Hz, 2H), 1.52-1.42 (m, 2H). LC-MScalcd exact mass 303.13, found m/z 304.4 [M+H]⁺.

Step 4: Methyl 2-(bromomethyl)-6-chlorobenzoate

To a solution of methyl 2-chloro-6-methylbenzoate (1 g, 5.4 mmol) incarbon tetrachloride (50 mL) was added N-bromosuccinimide (1 g, 5.9mmol) and benzoyl peroxide (0.131 g, 0.5 mmol). The resulting mixturewas stirred for 10 h at 80° C. The reaction mixture was filtered throughCelite, and the filtrate was evaporated under reduced pressure to affordmethyl 2-(bromomethyl)-6-chlorobenzoate (1.2 g). LC-MS calcd exact mass261.94, found m/z 263.0 [M+H]⁺.

Step 5: Methyl 2-(azidomethyl)-6-chlorobenzoate

To a solution of methyl 2-(bromomethyl)-6-chlorobenzoate (1 g, 3.8 mmol)in DMF (10 mL) was added sodium azide (0.494 g, 7.6 mmol) at 0° C. Theresulting mixture was stirred for 12 h at 70° C. The reaction mixturewas diluted with ice cold water (100 mL), and extracted with ethylacetate (2×100 mL). The combined organic layer was washed with brine (10mL), dried over sodium sulfate, filtered and evaporated under reducedpressure to afford methyl 2-(azidomethyl)-6-chlorobenzoate (1.2 g).LC-MS calcd exact mass 225.03, found m/z 198.1 [M+H-N₂].

Step 6: (2-(Aminomethyl)-6-chlorophenyl) methanol

To a solution of methyl 2-(azidomethyl)-6-chlorobenzoate (0.5 g, 2.2mmol) in tetrahydrofuran (10 mL) was slowly added lithium aluminumhydride (0.337 g, 8.8 mmol) at 0° C. The resulting mixture was stirredfor 12 h at room temperature. The reaction mixture was diluted with icecold water (50 mL), and extracted with ethyl acetate (2×100 mL). Thecombined organic layer was washed with brine (10 mL), dried over sodiumsulfate, filtered and evaporated under reduced pressure to afford(2-(aminomethyl)-6-chlorophenyl) methanol (0.4 g,). LC-MS calcd exactmass 171.05, found m/z 172.1 [M+H]⁺.

Step 7: N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl) amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a solution of1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid (0.1 g, 0.3 mmol) in DCM (10 mL) was added(2-(aminomethyl)-6-chlorophenyl) methanol (0.84 g, 0.4 mmol) and DIPEA(0.17 mL, 0.9 mmol) followed by T3P (0.24 mL, 0.8 mmol). The resultingmixture was stirred for 6 h at room temperature. The reaction mixturewas diluted with ice cold water (50 mL), and extracted with DCM (2×100mL). The combined organic layer was washed with brine (10 mL), driedover sodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by Biotage Isolera using methanol in DCM as eluentto afford N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl) amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (0.43g, 29%). HNMR (400 MHz, DMSO-d₆): δ 8.62 (t, J=6 Hz, 1H), 8.33 (s, 1H),8.25 (s, 1H), 8.10 (s, 1H), 7.36-7.23 (m, 4H), 5.24 (t, J=5.0 Hz, 1H),4.76 (d, J=5.2 Hz, 2H), 4.61 (d, J=6 Hz, 2H), 3.9 (br s, 1H), 3.83 (d,J=11.2 Hz, 2H), 3.36 (t, J=11.0 Hz, 2H), 2.17 (s, 3H), 1.80 (d, J=11.6Hz, 2H), 1.52-1.43 (m, 2H). LC-MS calcd exact mass 456.17, found m/z457.0 [M+H]⁺; HPLC purity 99.05%.

Representative Example for General Scheme 7 Example 14:N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide(Compound #77)

Step 1: 4-Bromo-N-phenylpyridin-2-amine

A solution of 4-bromopyridin-2-amine (1.0 g, 5.7 mmol), iodobenzene(2.35 g, 11.56 mmol) and cesium carbonate (8.82 g, 24.855 mmol) in1,4-dioxane was degassed with argon for 30 min, followed by the additionof Xantphos (0.66 g, 1.156 mmol) andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.528 g,0.578 mmol). The resulting mixture was stirred in sealed glass tube at150° C. for 12 h. The reaction mixture was cooled, combined with water(50 mL), and extracted with ethyl acetate (3×200 mL). Combined organiclayer was washed with water (100 mL) and brine (50 mL), dried oversodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by gradient column chromatography using ethylacetate in n-hexane as eluent to afford 4-bromo-N-phenylpyridin-2-amineas a yellow solid (0.81 g, 56%). LC-MS calcd exact mass 247.99 and249.99, found m/z 251.1 [M+H]⁺.

Step 2: Methyl1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate

To a solution of 4-bromo-N-phenylpyridin-2-amine (0.5 g, 2.00 mmol) inDMF (3 mL) was added methyl 1H-imidazole-4-carboxylate (0.37 g, 3.01mmol) and potassium phosphate (2.12 g, 10.00 mmol). The mixture wasdegassed with argon for 15 min, followed by the addition of copper(I)iodide (0.076 g, 0.40 mmol) and L-Proline (0.046 g, 0.40 mmol). Theresulting mixture was stirred in a sealed glass tube at 150° C. for 12h. The reaction mixture was cooled and combined with water (30 mL), andextracted with ethyl acetate (50 mL). The organic layer was dried oversodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by gradient column chromatography using ethylacetate in n-hexane as eluent to afford methyl1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate as acolorless solid (0.15 g, 25%). ¹HNMR (400 MHz, DMSO-d₆): δ 9.18 (s, 1H),8.45 (d, J 11.6 Hz, 2H), 8.25 (d, J 5.6 Hz, 1H), 7.64 (d, J 8 Hz, 2H),7.28 (t, J 7.2 Hz, 2H), 7.15 (d, J 4 Hz, 1H), 7.03 (s, 1H), 6.93 (t, J6.8 Hz, 1H), 3.79 (s, 3H) LC-MS calcd exact mass 294.11, found m/z 295.2[M+H]⁺.

Step 3: 1-(2-(Phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid

To a solution of methyl1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate (0.1 g, 0.77mmol) in THF (6 mL) and water (6 mL) was added lithium hydroxidemonohydrate (0.057 g, 1.36 mmol). The resulting mixture was stirred atRT for 6 h. The mixture was evaporated under reduced pressure, andadjusted to pH ˜6 by the addition of 1N HCl. The solid that formed wasremoved by filtration, washing with water (5 mL), and then dried underreduced pressure to afford1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid as acolorless solid (0.08 g, 88%). 1HNMR (400 MHz, DMSO-d₆): δ 12 (br s,1H), 9.30 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 8.24 (d, J 5.6 Hz, 1H),7.64 (d, J 8 Hz, 2H), 7.28 (t, J 7.6 Hz, 2H), 7.17 (d, J 1.6 Hz, 1H),7.06 (s, 1H), 6.94 (t, J 7.2 Hz, 1H). LC-MS calcd exact mass 280.10,found m/z 281.1 [M+H]⁺.

Step 4:N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide

To a solution of1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.04 g,0.178 mmol) in DCM (6 mL) and DMF (0.2 mL) was added triethylamine(0.053 mL, 0.534 mmol), EDC (0.068 g, 0.356 mmol) and HOBt (0.007 g,0.053 mmol). The reaction mixture was stirred at RT for 15 min and then2-amino-2-(3-chlorophenyl)ethanol (0.036 g, 0.213 mmol) was added. Themixture was stirred at RT for 12 h. The reaction mixture was combinedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by gradient column chromatography using methanol inDCM as eluent to affordN-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamideas a colorless solid (0.015 g, 24%). 1HNMR (400 MHz, DMSO-d₆): δ 9.17(s, 1H), 8.45 (s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.24 (d, J=7.6 Hz, 2H),7.64 (d, J=7.6 Hz, 2H), 7.42 (s, 1H), 7.32-7.28 (m, 2H), 7.27-7.25 (m,3H), 7.15 (d, J=5.6 Hz, 1H), 7.02 (s, 1H), 6.92 (t, J=7.2 Hz, 1H),5.04-4.99 (m, 2H), 3.73 (t, J=5.6 Hz, 2H). LC-MS calcd exact mass433.13, found m/z 434.2 [M+H]⁺. HPLC purity 99.52%; mp 130.0° C.

Representative Example for General Scheme 8 Example 15:1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3,5-dichloro-phenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide(Compound #74)

Step 1: 2-chloro-5-methylpyridine 1-oxide

To a solution of 2-chloro-5-methylpyridine (2.0 g, 15.7 mmol) in CHCl₃(20 mL) was added meta-chloroperoxybenzoic acid (3.2 g, 18.89 mmol)portion-wise, then the mixture was heated at 50° C. for 16 h. Thereaction mixture was cooled to −10° C., and the solid was filteredthrough Celite. The filtrate was evaporated and purified by columnchromatography over silica gel using 80% ethyl acetate in hexanes aseluent to give 2-chloro-5-methylpyridine 1-oxide (1.9 g, 84%). 1HNMR(400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.18 (d,J=8.4 Hz, 1H), 2.22 (s, 3H). LC-MS calcd exact mass 143.01, found m/z144.1 [M+H]⁺.

Step 2: 2-Chloro-5-methyl-4-nitropyridine 1-oxide

To a mixture of fuming nitric acid (4.5 mL) and sulfuric acid (6 mL) wasslowly added 2-chloro-5-methylpyridine-1-oxide (1.4 g, 9.7 mmol). Themixture was then heated at 100° C. for 2 h. The mixture was cooled toRT, poured into crushed ice, and then neutralized by the addition ofsolid sodium carbonate. The mixture was extracted with ethyl acetate,and the organic layer was dried over sodium sulfate, and evaporatedunder reduced pressure to give 2-chloro-5-methyl-4-nitropyridine 1-oxide(1.3 g, 72%). 1HNMR (400 MHz, CDCl₃): δ 8.27 (s, 1H), 8.26 (s, 1H), 2.60(s, 3H). LC-MS calcd exact mass 188.00, found m/z 189.1 [M+H]⁺.

Step 3: 5-Methyl-4-nitro-2-(phenylamino)pyridine 1-oxide

A mixture of 2-chloro-5-methyl-4-nitropyridine 1-oxide (0.5 g, 2.6mmol), aniline (0.5 g, 5.3 mmol), potassium carbonate (0.73 g, 5.3 mmol)in dioxane (10 mL) was purged with nitrogen gas for 30 min.Tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.13 mmol) and BINAP(0.16 g, 0.26 mmol) were added to the mixture, which was purged withnitrogen gas for another 20 min, and then was heated at 100° C. for 16h. The mixture was filtered through Celite, and the filtrate wasevaporated under reduced pressure. The residue was suspended in water,and extracted with ethyl acetate. The organic layer was dried oversodium sulfate, and evaporated under reduced pressure, and the residuewas purified by column chromatography over silica gel using 60% ethylacetate in hexane as eluent to give5-methyl-4-nitro-2-(phenylamino)pyridine 1-oxide. (0.4 g, 56%). 1HNMR(400 MHz, CDCl₃): δ 8.48 (s, 1H), 8.17 (s, 1H), 7.73 (s, 1H), 7.45 (t,J=8.4 Hz, 2H), 7.29-7.25 (m, 3H), 2.50 (s, 3H). LC-MS calcd exact mass245.08, found m/z 246.1 [M+H]⁺.

Step 4: 5-Methyl-N-2-phenylpyridine-2,4-diamine

Iron powder (0.53 g, 9.57 mmol) was added to a solution of5-methyl-4-nitro-2-(phenyl-amino)pyridine-1-oxide (0.35 g, 1.42 mmol) inacetic acid (7 mL), and the mixture was heated at 100° C. for 20 min.The mixture was cooled and then poured into 1M NaOH solution andextracted with DCM. The organic layer was washed with water and brine,dried over sodium sulfate, and evaporated under reduced pressure to give5-methyl-N-2-phenylpyridine-2,4-diamine (0.26 g, 93%). 1HNMR (400 MHz,DMSO-d₆): 8.75 (s, 1H), 7.52 (s, 1H), 7.38 (d, J=8 Hz, 2H), 7.25 (t,J=7.6 Hz, 2H), 6.92 (t, J=7.2 Hz, 1H), 6.26 (br s, 2H), 6.07 (s, 1H),1.93 (s, 3H). LC-MS calcd exact mass 199.11, found m/z 200.2 [M+H]⁺.

Step 5: 4-Bromo-5-methyl-N-phenylpyridin-2-amine

A mixture of copper(II) bromide (0.56 g, 2.51 mmol) and tert-butylnitrite (0.25 mL, 3.12 mmol) in acetonitrile (5 mL) was stirred at RTfor 30 min, cooled to 0° C., and then5-methyl-N-2-phenylpyridine-2,4-diamine (0.25 g, 1.25 mmol) was added.The mixture was stirred at RT for 1 h. The mixture was poured intowater, and extracted with ethyl acetate. The organic later was washedwith aqueous ammonium hydroxide solution (until blue color disappeared),water and brine. The organic layer was dried over sodium sulfate,evaporated under reduced pressure, and the residue was purified bycolumn chromatography over silica gel using 6% ethyl acetate in hexaneas eluent to give 4-bromo-5-methyl-N-phenylpyridin-2-amine (0.07 g,18%). 1HNMR (400 MHz, CDCl₃): 8.21 (s, 1H), 8.15 (s, 1H), 7.53-7.39 (m,4H), 7.04 (d, J=7.2 Hz, 2H), 2.39 (s, 3H). LC-MS calcd exact mass 262.01and 264.01, found m/z 265.1 [M+H]⁺.

Step 6:N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide

A mixture of 4-bromo-5-methyl-N-phenylpyridin-2-amine (0.07 g, 0.26mmol), N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide (0.07 g,0.29 mmol), potassium phosphate (0.16 g, 0.79 mmol) in DMF (2 mL) waspurged with nitrogen gas for 15 min. L-proline (0.006 g, 0.053 mmol) andcopper iodide (0.01 g, 0.053 mmol) were added to the reaction mixture,which was purged with nitrogen gas for another 10 min, and was thenheated in a sealed glass tube at 100° C. for 16 h. The mixture wascooled and suspended in water, and extracted with ethyl acetate. Organiclayer was dried over sodium sulfate and evaporated under reducedpressure, and the residue was purified by column chromatography oversilica gel using 2% methanol in DCM as eluent to giveN-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide(0.04 g, 40%). 1HNMR (400 MHz, DMSO-d₆): 9.04 (s, 1H), 8.13 (s, 1H),8.09 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J=8 Hz, 2H), 7.31 (t,J=7.2 Hz, 2H) 7.29-7.22 (m, 5H), 7.19-7.08 (m, 1H), 6.87 (t, J=7.6 Hz,1H), 6.74 (d, J=7.6 Hz, 2H), 5.06-5.01 (m, 1H), 4.85 (t, J=5.6 Hz, 1H),3.66-3.63 (m, 2H), 2.14 (s, 3H). LC-MS calcd exact mass 412.19, foundm/z 413.3 [M+H]⁺. HPLC purity 99.39%.

Representative Example for General Scheme 9 Example 16:N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide(Compound #159)

Step 1: Methyl1-(2-chloro-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate

To a stirred solution of methyl 1H-pyrrole-3-carboxylate (1.24 g, 9.97mmol) in DMF (15 mL) was added cesium carbonate (1.22 g, 3.72 mmol). Thereaction mixture was stirred at RT for 15 min, then2,4-dichloro-5-methylpyridine (2 g, 1.24 mmol) was added. The resultingmixture was heated at 100° C. for 10 h. The mixture was combined withwater (200 mL), and extracted with ethyl acetate (800 mL). The organiclayer was dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by gradient columnchromatography using ethyl acetate in n-hexane as eluent to affordmethyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate as acolorless solid (1.3 g, 43%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.44 (s, 1H),7.80 (s, 1H), 7.59 (s, 1H), 7.22 (t, J=2.0 Hz, 1H), 6.66-6.65 (m, 1H),3.73 (s, 3H), 2.25 (s, 3H). LC-MS calcd exact mass 250.05, found m/z251.1 [M+H]⁺.

Step 2: Methyl1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate

To a solution of methyl1-(2-chloro-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate (0.4 g, 1.60mmol) in dioxane (10 mL) was added potassium carbonate (0.66 g, 4.8mmol) and 4-fluoroaniline (0.26 g, 2.40 mmol). The mixture was degassedwith argon for 15 min, followed by the addition oftris(dibenzylideneacetone)dipalladium(0) (0.073 g, 0.08 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.09 g, 0.16mmol). The resulting mixture was stirred in a sealed glass tube at 100°C. for 12 h. The mixture was cooled and quenched with water (50 mL), andextracted with ethyl acetate (200 mL). The organic layer was dried oversodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by gradient column chromatography using ethylacetate in n-hexane as eluent to afford methyl1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylateas an off-white solid (0.4 g, 76%). 1HNMR (400 MHz, DMSO-d₆): δ 9.06 (s,1H), 8.12 (s, 1H), 7.69 (s, 1H), 7.64-7.60 (m, 2H), 7.14-7.07 (m, 3H),6.69 (s, 1H), 6.64-6.63 (m, 1H), 3.73 (s, 3H), 2.10 (s, 3H). LC-MS calcdexact mass 325.12, found m/z 326.2 [M+H]⁺.

Step 3:1-(2-((4-Fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylicacid

To a mixture of methyl1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate(0.5 g, 1.33 mmol) in THF (10 mL) and water (10 mL) was added lithiumhydroxide monohydrate (0.25 g, 6.15 mmol). The resulting mixture washeated to reflux for 12 h. The mixture was cooled and concentrated underreduced pressure, and adjusted to pH ˜6 by addition of 1N HCl. The solidwas removed by filtration, washing with water, and dried under vacuum toafford1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylicacid as an off-white solid (0.45 g, 94%). ¹HNMR (400 MHz, DMSO-d₆): δ9.16 (s, 1H), 8.11 (s, 1H), 7.62 (t, J 7.6 Hz, 3H), 7.11 (t, J 8.4 Hz,3H), 6.71 (s, 1H), 6.59 (s, 1H), 2.12 (s, 3H). LC-MS calcd exact mass311.11, found m/z 312.2 [M+H]⁺.

Step 4:N-((3-chlorophenyl)(cyano)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide

To a solution of1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylicacid (0.1 g, 0.32 mmol) in NMP (5 mL) was added triethylamine (0.09 g,0.96 mmol), EDC (0.12 g, 0.69 mmol) and HOBt (0.013 g, 0.096 mmol). Thereaction mixture was stirred at RT for 15 min, and then2-amino-2-(3-chlorophenyl)acetonitrile (0.064 g, 0.38 mmol) was added.The resulting mixture was stirred at RT for 12 h. The reaction mixturewas quenched with water (100 mL), and extracted with ethyl acetate (100mL). The organic layer was dried over sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by gradientcolumn chromatography using methanol in DCM as eluent to affordN-(3-chlorophenyl)(cyano)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamideas a colorless solid (0.03 g, 20%). 1HNMR (400 MHz, DMSO-d₆): δ 9.21 (d,J=8 Hz, 1H), 9.07 (s, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.64-7.60 (m,2H), 7.54 (s, 1H), 7.49 (s, 3H), 7.13 (s, 1H), 7.10 (t, J=8.8 Hz, 2H),6.75 (s, 1H), 6.68 (s, 1H), 6.40 (d, J=7.6 Hz, 1H), 2.13 (s, 3H). LC-MScalcd exact mass 459.13, found m/z 460.2 [M+H]⁺.

Step 5:N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide

To a solution ofN-(3-chlorophenyl)(cyano)methyl)-1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide(0.03 g, 0.065 mmol) in methanol (15 mL) was added Raney nickel (˜0.05g) under an argon atmosphere, and then methanolic ammonia (10 mL) wasadded.

The resulting mixture was stirred under an atmosphere of H₂ using abladder, at RT for 12 h. The reaction mixture was filtered throughCelite, washed with methanol (100 mL), and the filtrate was evaporatedunder reduced pressure. The residue was purified by gradient columnchromatography using methanol in DCM as eluent to affordN-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamideas a colorless solid (0.015 g, 50%). 1HNMR (400 MHz, DMSO-d₆): δ 9.07(s, 1H), 8.15-8.12 (m, 2H), 7.67-7.61 (m, 3H), 7.39 (s, 1H), 7.36-7.26(m, 3H), 7.09-7.06 (m, 3H), 6.75 (s, 1H), 6.69 (s, 1H), 4.90 (d, J=6.8Hz, 1H), 2.84 (d, J=7.2 Hz, 2H), 1.88 (br s, 2H), 2.14 (s, 3H). LC-MScalcd exact mass 463.16, found m/z 464.5 [M+H]⁺, HPLC purity 99.71%, mp118.1° C.

Representative Example for General Scheme 10 Example 17:1-(5-Chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide(Compound #106)

Step 1: Tert-butyl (4-chloropyridin-2yl)carbamate

To a stirred solution of 4-chloropyridin-2-amine (1.5 g, 1.16 mmol) inpyridine (15 mL), was added trimethylacetyl chloride (1.688 g, 1.4mmol). The mixture was stirred at RT overnight. The mixture was combinedwith water (20 mL) and extracted with ethyl acetate (3×40 ml). Thecombined organic layers were dried over sodium sulfate, then evaporatedunder reduced pressure and purified by gradient column chromatographybasic alumina using ethyl acetate in n-hexane as eluent to affordtert-N-(4-chloropyridin-2-yl)pivalamide as a white solid (1.7 g, 69%).¹HNMR (400 MHz, CDCl₃): δ 8.35 (s, 1H), 8.14 (d, J=5.6 Hz, 1H), 8.02 (brs, 1H), 7.04-7.02 (m, 1H), 1.32 (s, 9H).

Step 2: Tert-butyl (4,5-dichloropyridin-2-yl)carbamate

To a stirred solution of N-(4-chloropyridin-2-yl)pivalamide (1.6 g, 7.5mmol) in acetonitrile (40 mL) was added N-chlorosuccinimide (5.02 g,3.76 mmol). The mixture was stirred at reflux overnight. The mixture wascooled, combined with water (10 mL), and extracted with ethyl acetate(3×50 mL). The combined organic layers were dried over sodium sulfate,then evaporated under reduced pressure and purified by gradient columnchromatography using ethyl acetate in n-hexane as eluent to affordN-(4,5-dichloropyridin-2-yl)pivalamide as a white solid (1.3 g, 70%).¹HNMR (400 MHz, CDCl₃): δ 8.48 (s, 1H), 8.25 (s, 1H), 7.98 (br s, 1H),1.32 (s, 9H).

Step 3: 4,5-Dichloropyridin-2-amine

A mixture of N-(4,5-dichloropyridin-2-yl)pivalamide (1.25 g, 5.04 mmol)in 6N HCl (20 mL) was stirred at 100° C. for 10 h. The mixture wascooled, combined with water (20 mL), and basified by the addition ofsodium bicarbonate solution (20 mL). The mixture was extracted withethyl acetate (3×40 mL), and the combined organic layers were dried oversodium sulfate, then evaporated under reduced pressure and purified bygradient column chromatography using ethyl acetate in n-hexane as eluentto afford 4,5-dichloropyridin-2-amine as a white solid (0.7 g, 85%).¹HNMR (400 MHz, CDCl₃): δ 8.06 (s, 1H), 6.60 (s, 1H), 4.48 (br s, 2H).LC-MS calcd exact mass 161.98, found m/z 162.8 [M+H]⁺.

Step 4: 4, 5-Dichloro-N-phenylpyridin-2-amine

To a stirred solution of (4,5-dichloropyridin-2-amine (0.1 g, 0.61 mmol)in dioxane (5 mL) was added iodobenzene (0.25 g, 1.22 mmol), cesiumcarbonate (0.597 g, 1.83 mmol), and Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; 0.035 g, 0.06 mmol).The mixture was degassed with argon for 10 min, thentris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.03 mmol) was added,and the mixture was degassed again with argon for 10 min. The mixturewas stirred for 3 h at 100° C. The mixture was cooled, concentratedunder reduced pressure, diluted with water (10 mL) and extracted withethyl acetate (3×50 mL). The combined organic layer was washed withbrine (10 mL), dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by gradientcolumn chromatography using ethyl acetate in hexane as eluent to afford4,5-dichloro-N-phenylpyridin-2-amine as an off-white solid (82 mg, 56%yield). 1HNMR (400 MHz, CDCl₃): δ 8.17 (s, 1H), 7.36 (t, J=7.2 Hz, 2H),7.28 (s, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.92 (s, 1H), 6.51 (br s, 1H).LC-MS calcd exact mass 238.01, found m/z 239.1 [M+H]⁺.

Step 5: Methyl1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate

To a stirred solution of 4,5-dichloro-N-phenylpyridin-2-amine (0.3 g,1.25 mmol) in DMF (7 mL) was added potassium carbonate (0.867 g, 6.2mmol). The mixture was stirred at RT for 15 min, then methyl1H-imidazole-4-carboxylate (0.159 g, 1.25 mmol) was added, and themixture was stirred at 100° C. for 10 h. The mixture was cooled,combined with water (40 mL) and extracted with ethyl acetate (3×100 mL).The combined organic layers were dried over sodium sulfate, thenevaporated under reduced pressure, and the residue was purified bygradient column chromatography using ethyl acetate in n-hexane as eluentto afford methyl1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate asan off-white solid (103 mg, 25% yield). 1HNMR (400 MHz, DMSO-d₆): δ 9.44(s, 1H), 8.39 (s, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.14 (d, J=1.2 Hz, 1H),7.62-7.59 (m, 2H), 7.3 (t, J=5.2 Hz, 2H), 6.96 (t, J=8 Hz, 2H), 3.78 (s,3H). LC-MS calcd exact mass 328.07, found m/z 329.1 [M+H]⁺.

Step 4:1-(5-Chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid

To a stirred mixture of methyl1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate(0.075 g, 0.22 mmol) in THF (14 mL) and water (4 mL) was added lithiumhydroxide monohydrate (0.039 g, 0.91 mmol). The reaction mixture wasstirred at 50° C. overnight. The mixture was concentrated under reducedpressure, and neutralized to pH ˜7 by the addition of 1N HCl. The solidthat formed was removed by filtration to afford1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acidas a grey solid (35 mg, 49% yield). 1HNMR (400 MHz, DMSO): δ 9.45 (s,1H), 8.38 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.61 (d, J=8 Hz, 2H),7.29 (t, J=7.6 Hz, 2H), 6.97-6.93 (m, 2H). LC-MS calcd exact mass314.06, found m/z 315.1 [M+H]⁺.

Step 7:1-(5-Chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide

To a stirred solution of1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid(0.035 g, 0.11 mmol) in NMP (1.5 mL) was added EDC (0.065 g, 0.33 mmol),HOBt (0.005 g, 0.033 mmol), triethylamine (0.02 mL, 0.22 mmol), and2-amino-2-(3-chlorophenyl)ethanol (0.022 g, 0.13 mmol). The reactionmixture was stirred at RT overnight. The mixture was diluted with water(10 mL) and extracted with ethyl acetate (3×15 mL). The combined organiclayers were washed with brine (10 mL), dried over sodium sulfate, andevaporated under reduced pressure. The crude residue was purified bypreparative TLC using methanol in DCM as eluent to afford1-(5-chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamideas an off-white solid (19 mg, 36% yield). 1HNMR (400 MHz, DMSO-d₆): δ9.44 (s, 1H), 8.41 (s, 1H), 8.38 (d, J=4.0 Hz, 1H), 8.16 (s, 1H), 8.02(s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.44 (s, 1H), 7.33-7.30 (m, 2H),7.29-7.27 (m, 3H), 6.93 (s, 2H), 5.02-5.01 (m, 2H), 3.72 (t, J=5.6 Hz,2H). LC-MS calcd exact mass 467.09, found m/z 468.1 [M+H]⁺; HPLC purity99.88%.

Representative Example for General Scheme 11 Example 18:N-(2-amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide(Compound #191)

Step 1: Methyl1-(2-chloro-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate

To a solution of 2,4-dichloro-5-methylpyridine (1.285 g, 7.93 mmol) inDMF (15 mL) were added methyl 1H-imidazole-4-carboxylate (1 g, 7.93mmol) and K₂CO₃ (5.476 g, 39.68 mmol), and then the mixture was stirredat 100° C. for 6 h. The mixture was cooled and diluted with water, andthe solid that formed was removed by filtration and dried to obtaincrude product. The crude product was purified by Biotage Isolera (using50% ethyl acetate in hexane as eluent) to obtain methyl1-(2-chloro-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate (0.670 g,34%). 1HNMR (400 MHz, CDCl₃): δ 8.44 (s, 1H), 7.79 (s, 1H), 7.69 (s,1H), 7.27 (s, 1H), 3.94 (s, 3H), 2.28 (s, 3H). LC-MS calcd exact mass251.05, found m/z 252.1 [M+H]⁺.

Step 2: Methyl1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate

To a solution of methyl1-(2-chloro-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate (0.4 g,1.59 mmol) in dioxane (10 mL) were added 4-fluoroaniline (0.353 g, 3.18mmol) and K₂CO₃ (0.439 g, 3.18 mmol). The reaction mixture was degassedwith argon, then tris(dibenzylideneacetone)dipalladium(0) (0.072 g,0.079 mmol) and BINAP (0.099 g, 0.15 mmol) were added, and then themixture was heated at 100° C. for 1 h in the CEM microwave system. Themixture was cooled, diluted with water, and extracted with ethylacetate. The combined organic phases were washed with water and brine,dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography (using 4%methanol in DCM as eluent) to obtain methyl 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate (0.4 g, 77%).1HNMR (400 MHz, CDCl₃): δ 8.18 (s, 1H), 7.74 (s, 1H), 7.61 (s, 1H),7.29-7.25 (m, 2H), 7.06 (t, J=8 Hz, 2H), 6.55 (s, 1H), 5.29 (s, 1H),3.92 (s, 3H), 2.14 (s, 3H). LC-MS calcd exact mass 326.12, found m/z327.2 [M+H]⁺.

Step 3:1-(2-((4-Fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylicacid

To a solution of methyl1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate(0.450 g, 1.38 mmol) in THF (12 mL) was added LiOH (0.289 g, 6.90 mmol)in water (8 mL). The mixture was stirred at reflux overnight, and themixture was cooled, concentrated under reduced pressure, and neutralizedby the addition of 2N HCl. The reaction mixture was diluted with waterand extracted with ethyl acetate. The combined organic phases were driedover with sodium sulfate, filtered and evaporated under reduced pressureto obtain1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylicacid (0.210 g, 49%). 1HNMR (400 MHz, CDCl₃): δ 12.0 (br s, 1H), 9.15 (s,1H), 8.15 (d, J=11.2 Hz, 2H), 8.04 (s, 1H), 7.64-7.60 (m, 2H), 7.09 (t,J=17.2 Hz, 2H), 6.73 (s, 1H), 2.08 (s, 3H), LC-MS calcd exact mass312.10, found m/z 313.1 [M+H]⁺.

Step 4:N—(Cyano(phenyl)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide

To a solution of1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylicacid (0.2 g, 0.0641 mmol) in DCM (16 mL) were added2-amino-2-phenylacetonitrile (0.151 g, 0.0769 mmol), EDC (0.345 g, 0.128mmol), HOBt (0.040 g, 0.019 mmol), and TEA (0.194 g, 0.192 mmol).

The reaction mixture was stirred at RT for 24 h. Reaction mixture wasquenched with water and extracted with ethyl acetate. The organic phasewas dried over sodium sulfate, filtered and evaporated under reducedpressure to obtain crude product. The crude product was purified byBiotage Isolera (using 6% methanol in DCM as eluent) to giveN-(cyano(phenyl)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide(0.040 g, 15%). 1HNMR (400 MHz, CDCl₃): δ 8.36 (s, 1H), 8.12 (d, J=14.4Hz, 2H,), 7.63-7.60 (m, 3H), 7.52 (d, J=12 Hz, 2H), 7.45-7.34 (m, 4H),7.09 (t, J=8 Hz, 2H), 6.73 (s, 1H), 6.34 (d, J=8 Hz, 1H), 2.87 (s, 1H),2.08 (s, 3H). LC-MS calcd exact mass 426.16, found m/z 427.2 [M+H]⁺.

Step 5:N-(2-amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide

To a solution ofN-(cyano(phenyl)methyl)-1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide(0.04 g, 0.0094 mmol) in methanol (5 mL) was added Raney nickel (0.060g) and ammonium hydroxide (5 mL). The resulting reaction mixture wasstirred under hydrogen atmosphere using bladder for 6 h at RT. Thereaction mixture was filtered through Celite bed and washed withmethanol, and the filtrate was evaporated under reduced pressure. Theresidue was purified by preparative TLC (using 3.5% methanol in DCM aseluent) to obtain desired product (0.010 g, 25%). 1HNMR (400 MHz,DMSO-d₆): δ 9.14 (s, 1H), 8.45 (d, J=8.4 Hz, 8.15 (s, 1H), 8.08 (s, 1H),7.97 (s, 1H), 7.61 (t, J=8.4 Hz, 2H), 7.37-7.29 (m, 4H), 7.24-7.22 (m,1H), 7.11-7.06 (m, 2H), 6.72 (s, 1H), 4.98 (d, J=5.2 Hz, 1H), 3.06-2.93(m, 2H), 2.09 (s, 3H). LC-MS calcd exact mass 430.19, found m/z 431.5[M+H]⁺, HPLC purity 98.54%, mp 154.7° C.

Representative Example for General Scheme 12 Example 19:N-(1-cyano-2-phenylethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide(Compound #134)

Step 1: 4-Azido-2-chloro-5-methylpyridine

To a stirred solution of 2,4-dichloro-5-methylpyridine (1.0 g, 6.7 mmol)in DMF (15 mL) was added sodium azide (0.52 g, 8.1 mmol), and theresulting solution was then stirred at 100° C. for 4 h. Then the mixturewas cooled to 0° C., quenched with water (35 mL), and extracted withethyl acetate (3×25 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure, and theresidue (crude product, 1.2 g) was used in the next step withoutpurification.

Step 2: Methyl1-(2-chloro-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate

To a stirred solution of 4-azido-2-chloro-5-methylpyridine (1.0 g, 5.93mmol, crude) in DMSO (10 mL) plus H₂O (2 mL) was added CuSO₄.5H₂O (0.074g, 0.0297 mmol), methyl propiolate (0.499 g, 5.95 mmol), sodiumascorbate (0.117 g, 0.595 mmol), sodium carbonate (0.126 g, 1.19 mmol),and DL-proline (0.126 g, 1.19 mmol) at RT. The resulting mixture wasstirred at 65° C. for 18 h. Then the reaction mixture was cooled to 0°C., quenched with water (35 mL), and extracted with ethyl acetate (3×25mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure, and the residue was purified bycolumn chromatography using 40% ethyl acetate in n-hexane as eluent, togive desired product as a white solid (0.87 g, 56%). LC-MS calcd exactmass 252.04, found m/z 253.06 [M+H]⁺.

Step 3: Methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate

To a stirred solution of methyl1-(2-chloro-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate (0.4g, 1.58 mmol) in dioxane (20 mL) was added K₂CO₃ (0.438 g, 3.17 mmol),BINAP (0.098 g, 0.158 mmol), and 2,2-difluorobenzo[d][1,3]dioxol-5-amine(0.549 g, 3.17 mmol) at RT. The resulting solution was degassed withargon gas for 20 min, then Pd₂(dba)₃ (0.145 g, 0.18 mmol) was added, andthe reaction mixture was stirred at 100° C. for 8 h in a sealed glasstube. Then the reaction mixture was cooled to 0° C., quenched with water(35 mL), and extracted with ethyl acetate (3×25 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure, and the crude product residue was purified by columnchromatography using ethyl acetate in n-hexane as eluent to give desiredproduct as a white solid (0.43 g, 70%). LC-MS calcd exact mass 389.09,found m/z 388.19 [M−H]⁻.

Step 4: 1-(2-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylicacid

To a stirred solution of methyl1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate(0.24 g, 1.02 mmol) in THF:H₂O (5 mL:2 mL) was added LiOH (0.215 g, 5.14mmol), and then the reaction mixture was stirred at 80° C. for 4 h. Themixture was cooled to 0° C., acidified by the addition of 2 N HClsolution (10 mL), and then extracted with ethyl acetate (3×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure, to give desired product as ayellowish solid (0.21 g, 91%). LC-MS calcd exact mass 375.08, found m/z376.0 [M+H]⁺.

Step 5:N-(1-cyano-2-phenylethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide

To a stirred solution of1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylicacid (0.2 g, 0.533 mmol) in DCM (10 mL) was added EDC (0.2 g, 1.06mmol), triethylamine (0.18 mL, 1.33 mmol), and HOBt (0.1 g, 0.799 mmol).Then, 2-amino-3-phenylpropanenitrile (0.155 g, 1.066 mmol) was added andthe resulting mixture was stirred at RT for 18 h. The mixture wasquenched with water (20 mL), and extracted with ethyl acetate (3×20 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure, and the residue was purified bygradient chromatography using 60-120 mesh silica gel, eluting with 25%ethyl acetate in n-hexane, to give desired product as a yellowish solid(0.15 g, 56%).

Step 6:N-(1-amino-3-phenylpropan-2-yl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide

To a stirred solution ofN-(1-cyano-2-phenylethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide(0.13 g, 0.258 mmol) in methanol (10 mL) was added DCM (2 mL) to form aclear solution. To the solution was then added NiCl₂ (0.006 g, 0.051mmol) and NaBH₄ (0.049 g, 1.29 mmol), and the mixture was stirred at RTfor 14 h. The reaction mixture was quenched with water (20 mL), filteredthrough Celite, and extracted with DCM (3×20 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure, and the crude product residue was purified by gradientchromatography using 60-120 mesh silica gel, eluting with 8% MeOH inDCM, to give desired product as a yellowish solid (0.03 g, 23%). 1HNMR(400 MHz, DMSO-d₆): δ 11.29 (s, 1H), 9.49 (s, 1H), 9.04 (s, 1H), 8.59(d, J=8.8 Hz, 1H), 8.28 (s, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.33-7.14 (m,8H), 6.94 (d, J=9.6 Hz, 1H), 4.29 (s, 1H), 3.50 (s, 1H), 3.16-2.83 (m,3H), 1.97 (s, 3H). LC-MS calcd exact mass 507.18, found m/z 508.22[M+H]⁺; HPLC purity 97.94%.

Representative Example for General Scheme 13 Example 20:N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide(Compound #105)

Step 1: (S)-2-((4-Iodopyridin-2-yl)amino)butan-1-ol

To a stirred solution of 2-fluoro-4-iodopyridine (2.0 g, 8.97 mmol), inNMP (10 mL) was added (S)-2-aminobutan-1-ol (1.197 g, 13.45 mmol), thenthe mixture was stirred for 12 h at 100° C. in a sealed glass tube. Thenthe reaction mixture was cooled, quenched with water (50 mL), andextracted with ethyl acetate (3×80 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated under reducedpressure, and the residue was purified by gradient column chromatographyeluting with 20% ethyl acetate in n-hexane to give(S)-2-((4-iodopyridin-2-yl)amino)butan-1-ol, as an off-white solid, (0.8g, 30%). 1HNMR (400 MHz, DMSO-d₆): δ 7.61 (d, J=5.6 Hz, 1H), 6.91 (s,1H), 6.74-6.72 (m, 1H), 6.34 (d, J=8 Hz, 1H), 4.57 (t, J=6 Hz, 1H), 3.73(d, J=5.2 Hz, 1H), 3.42-3.38 (m, 1H), 3.31 (s, 1H), 1.60 (t, J=6 Hz,1H), 1.36 (t, J=7.2 Hz, 1H), 0.84 (t, J=7.6 Hz, 3H). LC-MS calcd exactmass 292.01, found m/z 293.0 [M+H]⁺.

Step 2: (S)-Methyl1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate

To a stirred solution of (S)-2-((4-iodopyridin-2-yl)amino)butan-1-ol(0.8 g, 1.71 mmol), in DMF (5 mL) was added potassium phosphate (0.32 g,2.57 mmol), methyl 1H-imidazole-4-carboxylate (0.323 g, 2.57 mmol), andL-proline (0.039 g, 0.34 mmol). The mixture was degassed with argon gasfor 20 min, then copper(I) iodide (0.065 g, 0.34 mmol) was added, andthen the mixture was stirred for 12 h at 150° C. in a sealed glass tube.Then the reaction mixture was cooled and quenched with water (35 mL),and extracted with ethyl acetate (3×60 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure, and the residue was purified by gradient column chromatographyeluting with 80% ethyl acetate in n-hexane to give (S)-methyl1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylateas an off-white semi-solid, (0.25 g, 32% yield). ¹HNMR (400 MHz,DMSO-d₆): δ 8.42 (s, 1H), 8.38 (s, 1H), 8.02 (d, J=6 Hz, 1H,), 7.67 (m,1H), 6.85 (m, 1H), 6.75 (s, 1H), 6.36 (d, J=8.4 Hz, 1H), 5.72 (s, 1H),4.61 (s, 1H), 4.12 (m, 1H), 3.81 (d, J=4 Hz, 1H), 3.78 (s, 3H), 3.46 (t,J=5.6 Hz, 1H), 3.34 (t, J=5.6 Hz, 2H), 1.60-1.44 (m, 1H), 1.33-1.24 (m,1H), 0.89-0.83 (m, 3H). LC-MS calcd exact mass 290.14, found m/z 291.2[M+H]⁺.

Step 3:(S)-1-(2-((1-Hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylicacid

To a stirred solution of (S)-methyl1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate(0.25 g, 0.86 mmol) in THF:water (5 mL:5 mL) was added lithium hydroxidemonohydrate (0.179 g, 4.29 mmol), and then the mixture was stirred for12 h at 50° C. The mixture was cooled and concentrated under reducedpressure, combined with water (15 mL), and washed with ethyl acetate(2×5 mL). The aqueous layer was adjusted to pH ˜6-6.5 by the addition of4N HCl, then the solid that formed was removed by filtration and driedunder high vacuum, to give desired product as an off-white solid (0.15g, 63% yield). 1HNMR (400 MHz, DMSO-d₆): δ 12.5 (br s, 1H), 8.32 (d,J=12 Hz, 2H), 8.02 (d, J=5.2 Hz, 1H), 6.84-6.82 (m, 1H), 6.74 (s, 1H),6.37 (d, J=8.4 Hz, 1H), 3.81 (d, J=5.6 Hz, 1H), 3.48-3.44 (m, 1H),1.67-1.60 (m, 1H), 1.46-1.40 (m, 1H), 1.37-1.31 (m, 1H), 1.26-1.24 (m,1H), 0.89-0.86 (m, 3H). LC-MS calcd exact mass 276.12, found m/z 277.2[M+H]⁺.

Step 4:N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of(S)-1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylicacid (0.07 g, 0.25 mmol) in NMP (3 mL), was added triethylamine (0.076g, 0.76 mmol), followed by EDC (0.097 g, 0.51 mmol) and HOBt (0.01 g,0.075 mmol). The mixture was stirred for 20 min at RT, and then2-amino-2-(3-chlorophenyl)ethanol (0.052 g, 0.30 mmol) was added, andthen the reaction mixture was stirred for 12 h at RT. The reactionmixture was quenched with water (25 mL), and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine(10 mL), dried over sodium sulfate, filtered and evaporated underreduced pressure and the residue was purified by gradient columnchromatography, eluting with 3% methanol in DCM, to giveN-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide,as an off-white solid, (15 mg, 14%). 1HNMR (400 MHz, DMSO-d₆): δ 8.38(t, J=7.2 Hz, 2H), 8.18 (s, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.42 (s, 1H),7.32-7.26 (m, 3H), 6.84 (d, J=5.6 Hz, 1H), 6.74 (s, 1H), 6.36 (d, J=7.6Hz, 1H), 5.02-4.99 (m, 2H), 4.61 (d, J=5.6 Hz, 1H), 3.81 (s, 1H), 3.71(t, J=5.6 Hz, 1H), 3.47-3.44 (m, 1H), 3.34-3.27 (m, 1H), 1.67-1.65 (m,1H), 1.63-1.61 (m, 1H), 1.07 (t, J=7.2 Hz, 1H), 0.87 (t, J=6.8 Hz, 3H).LC-MS calcd exact mass 429.16, found m/z 430.2 [M+H]⁺; HPLC Purity99.46%.

Example 21:N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide(Compound #163)

Step 1: N-(2,3-Dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine

To a suspension of 2,3-dihydrobenzofuran-5-amine (1 g, 7.4 mmol) in 1:1dioxane:water (200 mL) was added 2-fluoro-4-iodopyridine (1.982 g, 8.8mmol) and aqueous HCl (2 mL, 35%). The mixture was stirred for 15 h at100° C. in a sealed glass tube. Reaction mixture was cooled and basifiedby the addition of saturated aqueous sodium bicarbonate, and extractedwith ethyl acetate. The combined organic layers were dried over Na₂SO₄,filtered and evaporated to give crude product residue, which waspurified by gradient column chromatography using ethyl acetate inn-hexane as eluent to affordN-(2,3-dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine as yellow solid,(600 mg, 24%). 1HNMR (400 MHz, CDCl₃): δ 7.76 (d, J=4.8 Hz, 1H), 7.13(s, 1H), 7.00-6.97 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.48 (s, 1H), 4.60(t, J=8.8 Hz, 2H), 3.23 (t, J=8.8 Hz, 2H). LC-MS calcd exact mass337.99, found m/z 339.0 [M+H]⁺.

Step 2: Methyl1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate

To a solution of N-(2,3-dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine(300 mg, 0.88 mmol) in DMF (3 mL) was added methyl1H-imidazole-4-carboxylate (167 mg, 1.3 mmol), potassium phosphate (564mg, 2.6 mmol) and L-Proline (20 mg, 0.17 mmol) under a nitrogenatmosphere. The reaction mixture was purged with nitrogen for 10 min,then copper iodide (33 mg, 0.17 mmol) was added, and then the reactionmixture was stirred for 15 h at 140° C. in a sealed glass tube. Reactionmixture was cooled and filtered through Celite, and the filtrate wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄, filtered, and evaporated underreduced pressure, and the residue was purified by gradient columnchromatography using ethyl acetate in n-hexane as eluent to affordmethyl1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylateas a yellow semi-solid (0.10 g, 17%). LC-MS calcd exact mass 336.12,found m/z 337.2 [M+H]⁺.

Step 3:N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide

To a solution of methyl1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate(90 mg, 0.26 mmol) in toluene (3 mL) was added2-amino-2-(3-chlorophenyl)ethanol (91 mg, 5.3 mmol) andtrimethylaluminum in toluene (2M, 0.26 mL, 2 eq) under a nitrogenatmosphere. The mixture was stirred for 45 min at 100° C. in the CEMmicrowave. The reaction mixture was poured into ice water and extractedwith ethyl acetate. Combined organic layers were dried over Na₂SO₄,filtered and evaporated under reduced pressure to give a residue, whichwas purified by gradient column chromatography using methanol in DCM aseluent to affordN-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamideas an off-white solid (20 mg, 16%). 1HNMR (400 MHz, DMSO-d₆): δ 8.88 (s,1H), 8.42-8.37 (m, 2H), 8.20-8.16 (m, 2H), 7.51 (s, 1H), 7.42 (s, 1H),7.32-7.28 (m, 4H), 7.21 (d, J=8.4 Hz, 1H), 7.05 (d, J=4.8 Hz, 1H), 6.88(s, 1H), 6.8 (d, J=8.4 Hz, 1H), 5.02 (br s, 2H), 4.47 (t, J=8.8 Hz, 2H),3.72 (s, 2H), 3.15 (t, J=8.4 Hz, 2H). LC-MS calcd exact mass 475.14,found m/z 476.1 [M+H]⁺.

Representative Example for General Scheme 20 Example 22:(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Alternative Synthesis for Compound #225a)

Step 1: (S)-tert-butyl (1-(3-chlorophenyl)-2-hydroxyethyl)carbamate

To a stirred solution of (S)-2-amino-2-(3-chlorophenyl)ethanol (1.0 g,5.83 mmol) in t-butanol (15 mL) was added 2M sodium hydroxide solution(0.29 g, 7.28 mmol) and di-tert-butyl-dicarbonate (1.92 mL, 8.16 mmol).The reaction mixture was stirred at 70° C. for 16.0 h. The progress ofthe reaction was monitored by TLC (30% ethyl acetate in n-hexane, KMnO₄active). The reaction mixture was quenched with water (40 mL), extractedwith ethyl acetate (3×40 mL), and combined organic layers wereconcentrated under reduced pressure. The residue was purified bygradient chromatography, using 60-120 mesh silica gel, eluting with 20%ethyl acetate in in-hexane, collect the fractions and concentrated underreduced pressure, to afford (S)-tert-butyl(1-(3-chlorophenyl)-2-hydroxyethyl)carbamate, as a white solid (1.0 g,63%). ¹HNMR (400 MHz, DMSO-d₆): δ 7.32-7.21 (m, 5H), 4.78 (t, J=5.6 Hz,1H), 4.49 (d, J=5.6 Hz, 1H), 3.51-3.41 (m, 2H), 1.34 (s, 9H).

Step 2: (S)-2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl) ethylmethanesulfonate

To a stirred solution of (S)-tert-butyl(1-(3-chlorophenyl)-2-hydroxyethyl)carbamate (1.0 g, 3.68 mmol) indichloromethane (15 mL) was added triethyl amine (0.62 mL, 4.42 mmol),the mixture was cooled to 0° C. Methanesulfonyl chloride (0.313 mL,4.049 mmol) was added at 0° C., then the mixture was stirred at roomtemperature for 1.5 h. The progress of the reaction was monitored by TLC(25% ethyl acetate in n-hexane). The reaction mixture was quenched withsaturated ammonium chloride (20 mL), extracted with dichloromethane(3×30 mL), and the combined organic layers were dried over sodiumsulphate, filtered and concentrated under reduced pressure, washed withn-pentane and dried under vacuum, to afford(S)-2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)ethylmethanesulfonate, as a yellow oil, (0.65 g, 51%).

Step 3: (S)-tert-butyl (2-azido-1-(3-chlorophenyl)ethyl)carbamate

To a stirred solution of(S)-2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)ethylmethanesulfonate (0.65 g, 1.86 mmol), in N,N-dimethyl formamide (10 mL)was added sodium azide (0.242 g, 3.72 mmol) and the mixture was stirredat 50° C. for 16 h. The progress of the reaction was monitored by TLC(20% ethyl acetate in n-hexane). The reaction mixture was quenched withsaturated ammonium chloride (15 mL), followed by water (30 mL),extracted with ethyl acetate (3×30 mL), and combined organic layers wereconcentrated under reduced pressure. The residue was purified bygradient chromatography using 60-120 mesh silica gel, eluting with 8%ethyl acetate in n-hexane. The appropriate fractions were collected andconcentrated under reduced pressure, to afford (S)-tert-butyl(2-azido-1-(3-chlorophenyl)ethyl)carbamate, as a colorless oil, (0.5 g,91%). ¹HNMR (400 MHz, DMSO-d₆): δ 7.67-7.58 (m, 1H), 7.42 (br s, 1H),7.37-7.31 (m, 3H), 4.73 (br s, 1H), 3.44 (t, J=8.4 Hz, 2H), 1.35 (s,9H).

Step 4: (S)-2-azido-1-(3-chlorophenyl)ethanamine hydrochloride

To a stirred solution of (S)-tert-butyl(2-azido-1-(3-chlorophenyl)ethyl) carbamate (0.5 g, 1.69 mmol) indioxane (5 mL) was added 4M HCl in dioxane (10 mL) at 0° C. and themixture was stirred at room temperature for 16 h. The reaction mixturewas concentrated under reduced pressure, triturated with n-pentane anddried under vacuum, to afford (S)-2-azido-1-(3-chlorophenyl)ethanaminehydrochloride, as an off white solid, (0.43 g, HCl salt), LCMS calcdexact mass 196.05, m z found 197.1 [M+H]⁺.

Step 5:1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid

To a stirred solution of methyl1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate(10.0 g, 31.53 mmol) in tetrahydrofuran (450 mL), was added potassiumtrimethyl silanolate (12.13 g, 94.60 mmol) at 0° C., and the resultingmixture was stirred at 45° C. for 1.5 h. The progress of reaction wasmonitored by TLC (5% methanol in dichloromethane). The reaction mixturewas quenched with water (250 mL), washed with ethyl acetate (3×50 mL),then the aqueous layer was adjusted to pH 4-5 by addition of 4N HClsolution, extracted with 10% methanol in dichloromethane (8×250 mL), andcombined organic layers were concentrated under reduced pressure, toafford1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid, as an off white solid, (7.0 g, 73%). ¹HNMR (400 MHz, DMSO-d₆): δ12.46 (br s, 1H), 8.34 (s, 1H), 8.23 (br s, 1H), 8.20 (s, 1H), 7.36 (d,J=7.6 Hz, 1H), 3.89 (br s, 1H), 3.83 (d, J=11.6 Hz, 2H), 3.39-3.33 (m,2H), 2.16 (s, 3H), 1.80 (d, J=10.4 Hz, 2H), 1.52-1.42 (m, 2H). LCMScalcd exact mass 303.13, found m z 304.1 [M+H]⁺.

Step 6:(S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid (6.0 g, 19.80 mmol) in dichloromethane (150 mL) and N,N-dimethylformamide (50 mL) was added triethylamine (13.81 mL, 98.97 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.99 g, 59.40 mmol),hydroxybenzotriazole (0.605 g, 3.96 mmol) and(S)-2-azido-1-(3-chlorophenyl)ethanamine hydrochloride (4.65 g, 19.80mmol) under nitrogen atmosphere. The reaction mixture was stirred atroom temperature for 16 h. The progress of the reaction was monitored byTLC (5% methanol in dichloromethane). Then the reaction mixture wasquenched with saturated sodium bicarbonate solution (50 mL) andextracted with dichloromethane (3×50 mL), washed with water (100 mL) andbrine (50 mL). The combined organic layers were concentrated underreduced pressure. The residue was purified by gradient chromatographyusing 60-120 mesh silica gel, eluting with 4% methanol indichloromethane. The appropriate fractions were collected andconcentrated under reduced pressure to afford(S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamideas an off white solid (5.65 g, 59%). LCMS calcd exact mass 481.17, foundm z 482.1 [M+H]⁺.

Step 7: (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of(S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(7.12 g, 14.77 mmol) in methanol (75 mL) was added zinc dust (4.82 g,73.87 mmol), the resulting solution was stirred at room temperature for10 min, then added ammonium chloride (3.95 g, 73.87 mmol) in water (15mL). The reaction mixture was stirred at 55° C. for 1 h. The progress ofthe reaction was monitored by TLC (5% methanol in dichloro methane). Thereaction mixture was quenched with saturated sodium bicarbonate solution(50 mL) and filtered through celite, then washed with 10% methanol indichloromethane. The organic layer was washed with water (2×25 mL), andthe combined organic layers were concentrated under reduced pressure.The residue was purified by Biotage chromatography system using 60-120mesh silica gel, eluting with 13% (methanol/isopropylamine) indichloromethane. The appropriate fractions were collected andconcentrated under reduced pressure, to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,as an off white solid, (4.38 g, 65%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.52(d, J=8.0 Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.40 (s,1H), 7.36-7.25 (m, 4H), 4.92-4.87 (m, 1H), 3.86 (br s, 1H), 3.84-3.81(d, J=11.2 Hz, 2H), 3.33 (t, J=11.6 Hz, 2H), 2.97-2.92 (m, 1H),2.88-2.85 (m, 1H), 2.17 (s, 3H), 1.80 (d, J=11.6 Hz, 2H), 1.51-1.44 (m,4H). LCMS calcd exact mass 455.18, found m/z 456.1 [M+H]⁺. HPLC purity:99.47%, Chiral HPLC purity: 99.68%.

The Following Examples Illustrate the Preparation of Some of theCompounds: Example 23:(S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #259)

Step 1: Methyl1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

To a stirred solution of methyl1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (10.0 g,39.59 mmol) in isopropanol (60 mL) was added N,N-diisopropylethylamine(28.36 mL) and 3,3-difluorocyclobutanamine hydrochloride (6.81 g, 47.50mmol). The reaction mixture was stirred at 100° C. for 20 h in a sealedtube. The progress of the reaction was monitored by TLC (5% methanol indichloromethane). The reaction mixture was cooled to 0° C. and thecrystals that formed were filtered and dried under reduced pressure toafford compound methyl1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate,as an off-white solid, (23.0 g, 89%). LCMS calcd exact mass 323.12,found m z 324.2 [M+H]⁺.

Step 2:1-(2-((3,3-Difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylicacid

To a stirred solution of methyl1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate(30.5 g, 94.3 mmol) in THF (1.0 L) was added potassium trimethylsilanolate (48.38 g, 377.4 mmol) at 0° C., and the resulting reactionmixture was then stirred at room temperature for 1.5 h, using amechanical stirrer. The progress of the reaction was monitored by TLC(5% methanol in dichloromethane). The reaction mixture was quenched withwater (1.0 L), and washed with ethyl acetate (3×200 mL). The aqueousphase was adjusted to pH ˜3-4 by gradual addition of concentrated HCl,and the mixture was extracted with 10% methanol in dichloromethane(8×1.5 L). The combined organic layers were concentrated under reducedpressure, to afford1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylicacid, as an off white solid, (27.0 g, 93%). ¹HNMR (400 MHz, DMSO-d₆): δ12.50 (br s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 7.88 (d,J=6.0 Hz, 1H), 4.17 (t, J=6.4 Hz, 1H), 2.98-2.88 (m, 2H), 2.68-2.57 (m,2H), 2.18 (s, 3H). LCMS calcd exact mass 309.10, found m z 310.1 [M+H]⁺.

Step 3:(S)—N-(2-Azido-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methyl-pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylicacid (5.5 g, 17.79 mmol) in dichloromethane: N,N-dimethylformamide (150mL: 50 mL), was added N,N-diisopropylethylamine (15.49 mL, 88.98 mmol),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (6.82 g, 35.54 mmol),hydroxybenzotriazole (1.399 g, 88.99 mmol), and(S)-2-azido-1-(3-chlorophenyl)ethanamine hydrochloride (4.950 g, 19.41mmol), and then the mixture was stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC (5% methanol indichloromethane). The reaction mixture was quenched with water (500 mL),followed by addition of saturated sodium bicarbonate solution (50 mL),then extracted with ethyl acetate (3×250 mL). The combined organiclayers were dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by gradient chromatography using60-120 mesh silica gel, eluting at 3% methanol in dichloromethane. Thecollected fractions were concentrated under reduced pressure, to afford(S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methyl-pyrimidin-4-yl)-1H-imidazole-4-carboxamide,as a yellow gummy oil (6.0 g, 69%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.87 (d,J=9.2 Hz, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.86 (d, J=6.0Hz, 1H), 7.55 (s, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.36-7.28 (m, 2H), 5.25(d, J=5.2 Hz, 1H), 4.17 (t, J=6.4 Hz, 1H), 3.86 (t, J=12.0 Hz, 1H),3.65-3.60 (m, 1H), 2.95-2.90 (m, 2H), 2.67-2.60 (m, 2H), 2.20 (s, 3H).LCMS calcd exact mass 487.14, found m z 488.1 [M+H]⁺.

Step 4: (S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclo butyl) amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of(S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methyl pyrimidin-4-yl)-1H-imidazole-4-carboxamide (6.0 g, 12.30mmol) in methanol (100 mL), was added zinc dust (6.43 g, 98.38 mmol) andammonium chloride (5.35 g, 98.38 mmol) in water (25 mL), and then themixture was stirred at room temperature for 4 h. The progress of thereaction was monitored by TLC (5% methanol in dichloromethane). Thereaction mixture was quenched with ammonia solution (50 mL), filteredthrough celite, washed with 5% methanol in dichloromethane (25 mL), andthe organic layer was separated. The aqueous layer was extracted with 5%methanol in dichloromethane (3×80 mL), and the combined organic layerswere concentrated under reduced pressure. The residue was purified bygradient chromatography using 60-120 mesh silica gel, eluting with 8%(methanol/isopropylamine) in dichloromethane. Fractions were collectedand concentrated under reduced pressure, to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide,as a white solid (4.1 g, 72%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.54 (d,J=8.0 Hz, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.86 (d, J=5.6Hz, 1H), 7.40 (s, 1H), 7.35-7.25 (m, 3H), 4.93-4.88 (m, 1H), 4.17 (d,J=6.0 Hz, 1H), 2.90-2.84 (m, 4H), 2.68-2.55 (m, 2H), 2.20 (s, 3H), 1.54(br s, 2H). LCMS calcd exact mass 461.15, found m z 462.1 [M+H]⁺. HPLCpurity: 99.98%, Chiral HPLC: 99.97%, mp 104.3° C.

Example 24:(S)—N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #275)

Step 1: (S)-tert-Butyl (1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)carbamate

To a stirred solution of (S)-2-amino-2-(3-chloro-5-fluorophenyl)ethanolhydrochloride (10 g, 44.44 mmol) in t-butanol (100 mL) was added 2N NaOH(2.22 g, 55.55 mmol, in 111 mL water) and di-tert-butyl dicarbonate(13.56 g, 62.22 mmol). The resulting mixture was stirred at 70° C. for12 h. The progress of the reaction was monitored by TLC. Then thereaction was quenched with water (2×100 mL) and extracted with ethylacetate (2×100 mL), and the combined organic layers were washed withwater (30 mL) followed by brine (30 mL), dried over sodium sulfate,filtered and evaporated under reduced pressure to provide 13 g of crudeproduct. The crude product was combined with two additional crudeproduct batches that were prepared in a similar manner, and the combinedmaterial was purified by gradient column chromatography using ethylacetate in n-hexane as eluent to afford (S)-tert-butyl(1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)carbamate as an off whitesolid (94% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 7.26-7.23 (m, 2H), 7.20(s, 1H), 7.11 (d, J=8 Hz, 1H), 4.83 (t, J=4 Hz, 1H), 4.52-4.50 (m, 1H),3.50-3.43 (m, 2H), 1.34 (s, 9H). LC-MS calcd exact mass 289.74, found mz 190.0 [M+H-Boc]+.

Step 2:(S)-2-((tert-Butoxycarbonyl)amino)-2-(3-chloro-5-fluorophenyl)ethylmethanesulfonate

To a stirred solution of (S)-tert-butyl(1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl) carbamate (12 g, 41.52mmol) in dichloromethane (100 mL) at 0° C. was added triethylamine (6.93mL, 49.83 mmol) and the mixture was stirred for 10 min at 0° C. Thenmethane sulfonyl chloride (3.73 mL, 45.674 mmol) was added, and themixture was stirred at room temperature for 1 h. The progress of thereaction was monitored by TLC. The reaction was quenched with water (100mL) and extracted with dichloromethane (3×100 mL), and the combinedorganic layers were washed with saturated ammonium chloride solution(100 mL) and brine (50 mL). The organic layer was dried over sodiumsulfate, filtered and evaporated under reduced pressure to afford(S)-2-((tert-butoxycarbonyl)amino)-2-(3-chloro-5-fluorophenyl)ethylmethanesulfonate (15.25 g) as a light yellow solid, which was used forthe next step without further purification. ¹HNMR (400 MHz, DMSO-d₆): δ7.68 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 7.29 (d, J=9.6 Hz,1H), 4.28-4.19 (m, 2H), 3.15 (s, 3H), 1.36 (s, 9H). LC-MS calcd exactmass 367.07, found m z 268.0 [M+H-Boc]+.

Step 3: (S)-tert-Butyl(2-azido-1-(3-chloro-5-fluorophenyl)ethyl)carbamate

To a stirred solution of(S)-2-((tert-butoxycarbonyl)amino)-2-(3-chloro-5-fluorophenyl)ethylmethanesulfonate (15.25 g, 41.55 mmol) in N,N,-dimethylformamide (100mL) at room temperature was added sodium azide (5.4 g, 83.11 mmol). Thereaction mixture was heated at 60° C. for 12 h. The progress of thereaction was monitored by TLC, then the reaction mixture was cooled toroom temperature, diluted with water (100 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with water(100 mL) followed by brine (100 mL), and dried over sodium sulfate,filtered and evaporated under reduced pressure. The crude product wascombined with two additional crude product batches that were prepared ina similar manner, and the combined material was purified by gradientcolumn chromatography using ethyl acetate in n-hexane as eluent toafford (S)-tert-butyl(2-azido-1-(3-chloro-5-fluorophenyl)ethyl)carbamate as an off whitesolid (83% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 7.66 (d, J=8.0 Hz, 1H),7.31 (bs, 2H), 7.21 (d, J=12.0 Hz, 1H), 4.77-4.75 (m, 1H), 4.44 (d,J=8.0 Hz, 2H), 1.36 (s, 9H). LC-MS calcd exact mass 314.09, found m z259 [M+H-tBu]+.

Step 4: (S)-2-Azido-1-(3-chloro-5-fluorophenyl)ethanamine hydrochloride

To a stirred solution of (S)-tert-butyl (2-azido-1-(3-chloro-5-fluorophenyl)ethyl)carbamate (10 g, 31.85 mmol) in 1,4-dioxane (100 mL) wasadded drop wise 4M HCl in 1,4-dioxane (100 mL) at 0° C. The reactionmixture was stirred at room temperature for 3 h. Excess solvent wasevaporated under reduced pressure to obtain a solid residue. The solidwas washed with pentane (2×50 mL) and dried to give(S)-2-azido-1-(3-chloro-5-fluorophenyl) ethanamine hydrochloride (7.87g, 98.8%) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 8.94 (br s,3H), 7.56 (s, 1H), 7.49 (d, J=4.8 Hz, 2H), 4.55 (t, J=6.4 Hz, 1H),3.92-3.81 (m, 2H). LC-MS calcd exact mass 214.04, found m z 215.1[M+H]⁺.

Step 5:(S)—N-(2-Azido-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid (12.2 g, 40.26 mmol) in N,N′-dimethylformamide (120 mL) was addedtriethylamine (16.8 mL, 120.79 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (15.44 g, 80.53 mmol),hydroxybenzotriazole (3.08 g, 20.13 mmol) and(S)-2-azido-1-(3-chloro-5-fluorophenyl)ethanamine hydrochloride (8.01 g,32.21 mmol) under nitrogen atmosphere. The resulting mixture was stirredat room temperature for 16 h. The progress of the reaction was monitoredby TLC (8% methanol in dichloromethane). The reaction mixture wasdiluted with water (2×100 mL) and extracted with ethyl acetate (2×100mL). The combined organic layers were washed with saturated ammoniumchloride solution (1×200 mL), followed by saturated sodium bicarbonatesolution (1×200 mL) and brine (1×50 mL). The organic layer was driedover sodium sulfate, filtered and concentrated under reduced pressure togive the desired crude product. The crude product was combined with twoadditional crude product batches that were prepared in a similar manner,and the combined material was purified by gradient column chromatographyusing methanol in dichloromethane as eluent to afford(S)—N-(2-azido-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(69%) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 8.90 (d, J=8.8Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.42 (s, 1H),7.34-7.31 (m, 3H), 5.29-5.23 (m, 1H), 3.86 (br s, 1H), 3.85-3.84 (m,3H), 3.66-3.62 (m, 1H), 3.36 (t, J=10.8 Hz, 2H), 2.17 (s, 3H), 1.80 (d,J=10.8 Hz, 2H), 1.51-1.44 (m, 2H). LCMS calcd exact mass 499.16, found mz 500.1 [M+H]⁺.

Step 6:(S)—N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of(S)—N-(2-azido-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(9.0 g, 18.04 mmol) in methanol (100 mL) was added zinc dust (5.89 g,90.18 mmol), followed by ammonium chloride (4.823 g, 90.18 mmol) inwater (20 mL) at 0° C., then the mixture was stirred at room temperaturefor 3 h. The progress of the reaction was monitored by TLC (8% methanolin dichloromethane). The reaction mixture was quenched with saturatedsodium bicarbonate solution (100 mL) and methanol (100 mL), thenfiltered through celite, washing with methanol. The filtrate wasevaporated and diluted with 50 mL sodium bicarbonate, and extracted withDCM (3×100 mL). The combined organic layers were dried over sodiumsulfate, filtered and evaporated to give the crude product. The crudeproduct was combined with two additional crude product batches that wereprepared in a similar manner, and the combined material was purified bygradient column chromatography using methanol in dichloromethane with0.1% isopropylamine as eluent, to afford(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(18.5 g, 55%) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 8.58(d, J=8 Hz, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.35 (d,J=7.2 Hz, 1H), 7.28-7.25 (m, 2H), 7.19 (d, J=9.2 Hz, 1H), 4.93-4.90 (m,1H), 3.90 (br s, 1H), 3.83 (d, J=11.6 Hz, 2H), 3.36 (t, J=10.8 Hz, 2H),2.95-2.95 (m, 1H), 2.91-2.88 (m, 1H), 2.17 (s, 3H), 1.98-1.9 (br s, 2H),1.80 (d, J=12 Hz, 2H), 1.50-1.46 (m, 2H), LCMS calcd exact mass 473.17,found m z 474.2 [M+H]⁺. HPLC purity: 99.79%, Chiral HPLC purity: 99.92%.

Example 25:N-(3-Chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(Compound #297)

Step 1: 2-Chloro-4-fluoro-6-methylbenzoic acid

To a stirred solution of 4-fluoro-2-methylbenzoic acid (5.0 g, 32.46mmol) in N,N-dimethyl-formamide (20 mL) was added palladium acetate(1.74 g, 2.59 mmol), and N-chlorosuccinimide (6.4 g, 48.70 mmol) thenthe mixture was stirred at 100° C. for 16 h. The reaction mixture wascooled and diluted with saturated sodium thiosulfate solution (200 mL),extracted with ethyl acetate (2×500 mL), and the combined organic layerswere washed with brine (50 mL), concentrated under reduced pressure, anddried under vacuum to afford a mixture of2-chloro-4-fluoro-6-methylbenzoic acid and 4-fluoro-6-methylbenzoicacid, as a brown solid (5 g, crude product mixture) that was used in thenext step without purification. LC-MS calcd exact mass for2-chloro-4-fluoro-6-methylbenzoic acid 188.0, found m z 189.1 [M+H]⁺.

Step 2: 2-Chloro-4-fluoro-6-methylbenzoic acid

To a stirred solution of 2-chloro-4-fluoro-6-methylbenzoic acid and4-fluoro-6-methylbenzoic acid (5 g) in methanol (100 mL) was slowlyadded dropwise thionyl chloride (11.6 mL, 159.5 mmol) at 0° C., then thereaction mixture was stirred at 85° C. for 2 h. The reaction mixture wasevaporated and quenched with saturated sodium bicarbonate solution (100mL), extracted with ethyl acetate (2×300 mL), then aqueous layer wasadjusted to pH ˜6-7 by addition of concentrated HCl, then the compoundwas extracted with ethyl acetate (2×300 mL), combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, concentrated underreduced pressure to afford 2-chloro-4-fluoro-6-methylbenzoic acid as abrown solid (2 g), which was used without further purification. LC-MScalcd exact mass 188.0, found m z 189.0 [M+H]⁺.

Step 3: Methyl 2-chloro-4-fluoro-6-methylbenzoate

To a stirred solution of 2-chloro-4-fluoro-6-methylbenzoic acid (2 g,10.63 mmol) in N,N-dimethylformamide (15 mL) was added potassiumcarbonate (2.9 g, 21.27 mmol) and methyl iodide (3.3 mL, 53.19 mmol) at0° C., and the mixture was stirred at room temperature for 2 h. Theprogress of the reaction was monitored by TLC. The reaction mixture wasquenched with water (50 mL), extracted with ethyl acetate (2×100 mL),and the combined organic layers were washed with brine (20 mL), driedover sodium sulfate and concentrated under reduced pressure to affordmethyl 2-chloro-4-fluoro-6-methylbenzoate as a colorless oil (2 g),which was used without further purification. LC-MS calcd exact mass202.02, found m z 203.0 [M+H]⁺.

Step 4: Methyl 2-(bromomethyl)-6-chloro-4-fluorobenzoate

To a stirred solution of methyl 2-chloro-4-fluoro-6-methylbenzoate (2 g,9.9 mmol) in carbon tetrachloride (5 mL) was added N-bromosuccinimide(1.9 g, 10.8 mmol) and benzoyl peroxide (0.239 g, 0.99 mmol). Theresulting mixture was stirred for 12 h at 80° C. The progress of thereaction was monitored by TLC. The reaction mixture was quenched with 1%sodium hydroxide solution (50 mL), extracted with ethyl acetate (2×200mL), and the combined organic layers were washed with brine (20 mL),dried over sodium sulfate and concentrated under reduced pressure toafford methyl 2-(bromomethyl)-6-chloro-4-fluorobenzoate as a brownliquid (2 g, crude product). LC-MS calcd exact mass 279.93, found m z281.0 [M+H]⁺.

Step 5: Methyl 2-(azidomethyl)-6-chloro-4-fluorobenzoate

To a stirred solution of methyl2-(bromomethyl)-6-chloro-4-fluorobenzoate (2 g, 7.16 mmol) inN,N-dimethylformamide (10 mL) was added sodium azide (0.931 g, 14.33mmol) at 0° C. The resulting mixture was stirred for 6 h at 70° C. Theprogress of the reaction was monitored by TLC. The reaction mixture wasdiluted with ice cold water (100 mL), and extracted with ethyl acetate(2×200 mL). The combined organic layer was washed with brine (10 mL),dried over anhydrous sodium sulfate, filtered and evaporated underreduced pressure to afford methyl2-(azidomethyl)-6-chloro-4-fluorobenzoate as a brown solid (1.5 g, crudeproduct). LC-MS calcd exact mass 243.02, found m z 218.0 for [M−N₂+H₃].

Step 6: (2-(Aminomethyl)-6-chloro-4-fluorophenyl)methanol

To a stirred solution of methyl2-(azidomethyl)-6-chloro-4-fluorobenzoate (0.2 g, 0.823 mmol) in THF (10mL) was added lithium aluminum hydride (0.108 g, 3.29 mmol) at 0° C.slowly. The resulting mixture was stirred for 12 h at room temperature.The progress of reaction was monitored by TLC. The reaction mixture wasdiluted with ice cold water (50 mL), and extracted with ethyl acetate(2×200 mL). The combined organic layer was washed with brine (10 mL),dried over anhydrous sodium sulfate, filtered and evaporated underreduced pressure to afford(2-(aminomethyl)-6-chloro-4-fluorophenyl)methanol (0.2 g, crudeproduct). LC-MS calcd exact mass 189.04, found m z 190.1 [M+H]⁺.

Step 7:N-(3-Chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

To a stirred solution of1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylicacid (0.1 g, 0.33 mmol) in dichloromethane (10 mL) was added(2-(aminomethyl)-6-chloro-4-fluorophenyl)methanol (0.093 g, 0.495 mmol),N,N-diisopropylethylamine (0.16 mL, 0.9 mmol) followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.075 g, 0.396 mmol) andhydroxybenzotriazole (0.06 g, 0.396 mmol). The resulting mixture wasstirred for 12 h at room temperature. The progress of the reaction wasmonitored by TLC. The reaction mixture was diluted with ice cold water(50 mL), and extracted with dichloromethane (2×200 mL). The combinedorganic layer was washed with brine (10 mL), dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by using a Biotage Isolera system using methanol indichloromethane as eluent to affordN-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamideas an off-white solid (0.015 g, 9.5%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.73(t, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.35 (d, J=7.6 Hz,1H), 7.30-7.28 (m, 1H), 7.10-7.07 (m, 1H), 5.22 (t, 1H), 4.71 (d, J=5.2Hz, 2H), 4.60 (d, J=6 Hz, 2H), 3.89 (s, 1H), 3.83 (d, J=10.8 Hz, 2H),3.39-3.32 (m, 2H), 2.17 (s, 3H), 1.82 (t, 2H), 1.53-1.44 (m, 2H). LC-MScalcd exact mass 474.16, found m z 475.1 [M+H]⁺. HPLC purity 98.2%.

Example 26: (S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide hydrochloride salt (Compound#298)

To a solution of(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(0.1 g, 0.21 mmol) in 1,4-dioxane (10 mL) was slowly added 4M HCl in1,4-dioxane (0.05 mL, 0.22 mmol) at 0° C. The reaction mixture wasstirred for 1.0 h at room temperature. The reaction mixture wasevaporated, washed with diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidehydrochloride salt as an off-white solid (0.1 g, 93%). ¹HNMR (400 MHz,DMSO-d₆): δ 8.90 (d, J=9.2 Hz, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.14 (s,1H), 7.97 (br s, 3H), 7.51 (s, 1H), 7.42-7.37 (m, 4H), 5.32 (d, J=4.4Hz, 1H), 3.83 (d, J=11.6 Hz, 3H), 3.38-3.35 (m, 2H), 3.31-3.23 (m, 2H),2.16 (s, 3H), 1.80 (d, J=12.8 Hz, 2H), 1.49 (t, 2H). LC-MS calcd exactmass 455.18, found m z 456.2 for [M+H]⁺. HPLC purity 98.79%, Meltingpoint: 193-195° C.

Example 27:(S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidep-toluenesulfonic acid salt (Compound #299)

To a solution of(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (0.1 g,0.21 mmol) in 1,4-dioxane (6 mL) was added p-toluenesulfonic acidmonohydrate (0.041 g, 0.22 mmol) slowly at 0° C. The reaction mixturewas stirred for 1 h at room temperature. The reaction mixture wasevaporated, washed with diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidep-toluenesulfonic acid as an off-white solid (0.104 g, 74%). ¹HNMR (400MHz, DMSO-d₆): δ 8.81 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.29 (s, 1H),8.11 (s, 1H), 7.46 (t, 2H), 7.41-7.35 (m, 4H), 7.09-7.07 (br s, 3H),5.24 (d, J=4 Hz, 1H), 3.85-3.82 (m, 3H), 3.38-3.27 (m, 3H), 3.18-3.13(m, 1H), 2.30 (s, 3H), 2.16 (s, 2H), 1.80 (d, J=11.6 Hz, 2H), 1.52-1.44(m, 2H). LC-MS calcd exact mass 455.18, found m z 456.2 for [M+H]⁺. HPLCpurity 99.32%.

Example 28:(S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidebenzenesulfonic acid salt (Compound #300)

To a solution of(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(6 g, 13.18 mmol) in 1,4-dioxane (360 mL) was slowly addedbenzenesulfonic acid (2.08 g, 13.18 mmol) at 0° C. The reaction mixturewas stirred for 1 h at room temperature. The reaction mixture wasevaporated, washed with diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidebenzenesulfonic acid salt as an off-white solid (6 g, 74%). Meltingpoint: 141-142.5° C. ¹HNMR (400 MHz, DMSO-d₆): δ 8.89 (d, J=9.2 Hz, 1H),8.35 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.91 (br s, 3H), 7.58 (d,J=5.6 Hz, 2H), 7.51 (s, 1H), 7.42-7.35 (m, 4H), 7.28 (d, J=6 Hz, 3H),5.34-5.31 (m, 1H), 3.85-3.82 (m, 3H), 3.41-3.32 (m, 3H), 3.28 (s, 1H),2.16 (s, 3H), 1.80 (d, J=11.6 Hz, 2H), 1.49 (t, 2H). LC-MS calcd exactmass 455.18, found m z 456.2 for [M+H]⁺. HPLC purity 98.63%.

Example 29:(S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamidehydrochloride salt (Compound #301)

To a stirred solution of(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)-amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide(1 g, 2.16 mmol) in 1,4-dioxane (20 mL) was slowly added 4M HCl indioxane (0.54 mL, 2.16 mmol) at 0° C. The reaction mixture was stirredfor 1 h at room temperature. The reaction mixture was evaporated, washedwith diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methyl-pyrimidin-4-yl)-1H-imidazole-4-carboxamidehydrochloride salt as an off-white solid (1 g, 93%). ¹HNMR (400 MHz,DMSO-d₆): δ 8.90 (d, J=8.8 Hz, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.18 (s,1H), 7.88 (d, J=4.8 Hz, 1H), 7.62 (br s, 3H), 7.50 (s, 1H), 7.38-7.35(m, 3H), 5.29 (d, J=4 Hz, 1H), 4.16 (s, 1H), 3.39-3.28 (m, 1H),3.18-3.14 (m, 1H), 2.92 (t, 2H), 2.61 (t, 2H), 2.19 (s, 3H). LC-MS calcdexact mass 461.15, found m z 462.1 for [M+H]⁺. HPLC purity 99.81%,Melting point: 213-216° C.

Example 30:(S)—N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidebenzenesulfonic acid salt (Compound #302)

To a stirred solution of(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(0.2 g, 0.422 mmol) in 1,4-dioxane (10 mL) was slowly addedbenzenesulfonic acid (0.066 g, 0.422 mmol) at 0° C. The reaction mixturewas stirred for 1 h at room temperature. The reaction mixture wasevaporated, washed with diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidebenzenesulfonicacid salt as an off-white solid (0.22 g, 83%). ¹HNMR (400 MHz, DMSO-d₆):δ 8.92 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.83(br s, 3H), 7.57 (d, J=6.4 Hz, 2H), 7.37 (s, 3H), 7.28 (d, J=6.4 Hz,4H), 5.32 (d, J=4.4 Hz, 1H), 3.83 (d, J=11.6 Hz, 3H), 3.41-3.27 (m, 3H),3.18-3.14 (m, 1H), 2.16 (s, 3H), 1.80 (d, J=12 Hz, 2H), 1.52-1.44 (m,2H). LC-MS calcd exact mass 473.17, found m z 474.2 [M+H]⁺. HPLC purity99.85%, Melting point: 161-162° C.

Example 31:(S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamidep-toluenesulfonic acid salt (Compound #303)

To a stirred solution of(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)-amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide(0.1 g, 2.16 mmol) in 1,4-dioxane (6 mL) was slowly addedp-toluenesulfonic acid monohydrate (0.041 g, 2.16 mmol) at 0° C. Thereaction mixture was stirred for 1 h at room temperature. The reactionmixture was evaporated, washed with diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamidep-toluenesulfonic acid salt as an off-white solid (0.11 g, 78%). ¹HNMR(400 MHz, DMSO-d₆): δ 8.88 (d, J=9.2 Hz, 1H), 8.39 (s, 1H), 8.32 (s,1H), 8.14 (s, 1H), 7.87 (d, J=5.2 Hz, 2H), 7.75 (br s, 3H), 7.51 (s,1H), 7.46-7.42 (m, 2H), 7.40-7.35 (m, 3H), 7.08 (d, J=7.6 Hz, 2H), 5.31(d, J=4.4 Hz, 1H), 4.16 (s, 1H), 3.40-3.27 (m, 1H), 3.24-3.19 (m, 1H),2.92 (t, 2H), 2.61 (t, 2H), 2.26 (s, 3H), 2.19 (s, 3H). LC-MS calcdexact mass 461.15, found m/z 462.1 for [M+H]⁺. HPLC purity 98.11%,Melting point: 150-151° C.

Example 32:(S)—N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamidebenzenesulfonic acid salt (Compound #304)

To a stirred solution of(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclo-butyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide(0.25 g, 0.541 mmol) in 1,4-dioxane (12 mL) was slowly addedbenzenesulfonic acid (0.085 g, 0.541 mmol) at 0° C. The reaction mixturewas stirred for 1.0 h at room temperature. The reaction mixture wasevaporated, washed with diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamidebenzenesulfonic acid salt as an off-white solid (0.28 g, 83%). ¹HNMR(400 MHz, DMSO-d₆): δ 8.88 (d, J=8.8 Hz, 1H), 8.39 (s, 1H), 8.32 (s,1H), 8.14 (s, 1H), 7.87 (d, J=4.8 Hz, 1H), 7.72 (br s, 3H), 7.57 (d, J=6Hz, 2H), 7.51 (s, 1H), 7.42-7.37 (m, 3H), 7.28 (d, J=6.4 Hz, 3H), 5.31(d, J=4.4 Hz, 1H), 4.16 (s, 1H), 3.39-3.27 (m, 1H), 3.23 (d, J=4.8 Hz,1H), 2.92 (t, 2H), 2.63 (d, J=12 Hz, 2H), 2.19 (s, 3H). LC-MS calcdexact mass 461.15, found m z 462.1 for [M+H]⁺. HPLC purity 99.82%,Melting point: 155-156° C.

Example 33:(S)—N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidehydrochloride salt (Compound #305)

To a stirred solution of(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide(0.05 g, 0.105 mmol) in 1,4-dioxane (3 mL) was slowly added 4M HCl indioxane (0.02 mL, 0.105 mmol) at 0° C. The reaction mixture was stirredfor 1.0 h at room temperature. The reaction mixture was evaporated,washed with diethyl ether and dried to afford(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamidehydrochloride salt as an off white solid (0.05 g, 94%). ¹HNMR (400 MHz,DMSO-d₆): δ 8.95 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.15 (s,1H), 8.00 (br s, 3H), 7.37 (br s, 3H), 7.28 (d, J=9.6 Hz, 1H), 5.33 (t,1H), 3.85-3.82 (m, 3H), 3.37-3.33 (m, 3H), 3.25 (t, 1H), 2.16 (s, 3H),1.80 (d, J=11.6 Hz, 2H), 1.52-1.44 (m, 2H). LC-MS calcd exact mass473.17, found m z 474.2 for [M+H]⁺. HPLC purity 99.86%, Melting point:210-211° C.

The following Table 1 provides a summary of the synthetic methodsutilized to prepare the compounds of the present invention identifiedtherein, by reference to the Schemes described above, and data obtainedand utilized in the characterization of the prepared compounds. In somecases, the synthetic method used was a combination of two differentmethods, as indicated in the Table by reference to two Scheme numbers.In certain other cases, the method utilized was a slight variation ofthe method referenced by the Scheme number; such variation would beapparent to one skilled in the art. In certain other cases, thesynthetic method was as indicated by the Scheme number in the Table,followed by further slight chemical modification using methodology wellknown to those skilled in the art.

TABLE 1 Cmpd Scheme # Structure Name NMR data #  1

(S)-1-(1-(3- chlorophenyl)-2- hydroxyethyl)-3- (1-(2-((2-chloro-phenyl)amino) pyrimidin-4-yl)- 1H-pyrazol-4-yl) urea 1HNMR (400 MHz,DMSO-d₆): δ 9.02 (s, 1H), 8.66 (s, 1H), 8.39 (s 1H), 8.38 (s, 1H), 7.79(s, 1H), 7.74 (d, J = 8 Hz, 1H), 7.49 (d, J = 7.99 Hz, 1H), 7.52-7.34(m, 2H), 7.31-7.26 (m, 2H), 7.19-7.15 (m, 2H), 6.83 (d, J = 7.59 Hz,1H), 4.98 (s, 1H), 4.74-4.72 (m, 1H), 3.64-3.56 (m, 2H)  1  2

(S)-1-(1-(3- chlorophenyl)-2- hydroxyethyl)-3- (1-(2-((2-chloro-phenyl)amino)-5- methylpyrimidin- 4-yl)-1H-pyrazol- 4-yl)urea 1HNMR (400MHz, DMSO-d₆): δ 8.79 (s, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H),7.79 (s, 1H), 7.78 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.35-7.26 (m, 4H),7.13 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 4.99-4.91 (m, 1H),4.74-4.72 (m, 1H), 3.65-3.55 (m, 2H), 2.41 (s, 3H)  1  3

(S)-1-(1-(3- chlorophenyl)-2- hydroxyethyl)-3- (1-(2-(cyclo-propyl-amino)- 5-methyl- pyrimidin-4-yl)- 1H-pyrazol-4- yl)urea 1HNMR(400 MHz, DMSO-d₆): δ 8.61 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.72 (s,1H), 7.34-7.26 (m, 4H), 6.77 (d, J = 7.6 Hz, 1H), 4.97 (s, 1H),4.73-4.71 (m, 1H), 3.62-3.57 (m, 2H), 2.67-2.66 (m, 1H), 2.34 (s, 3H),0.63 (d, J = 5.2 Hz, 2H), 0.44 (s, 2H)  1  4

(R)-1-(1-(2-((2- chlorophenyl) amino) pyrimidin- 4-yl)-1H-pyrazol-4-yl)- 3-(2-hydroxy- 1-phenylethyl) urea 1HNMR (400 MHz,DMSO-d₆): 9.01 (s, 1H), 8.63 (s, 1H), 8.38 (d, J = 6.4 Hz, 2H), 7.78 (s,1H), 7.74 (d, J = 8 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 7.34-7.29 (m, 4H),7.22-7.15 (m, 3H), 6.73 (d, J = 8 Hz, 1H), 4.92 (s, 1H), 4.73-4.70 (m,1H), 3.63-3.54 (m, 2H)  1  5

1-(1-(2-((2- chlorophenyl) amino) pyrimidin-4- yl)-1H- pyrazol-4-yl)-3-(1-(3-chloro- phenyl)ethyl) urea 1HNMR (400 MHz, DMSO-d₆): δ 9.02 (s,1H), 8.45 (s, 1H), 8.45-8.39 (m, 2H), 7.79 (s, 1H), 7.74 (d, J = 7.99Hz, 1H), 7.49 (d, J = 7.59 Hz, 1H), 7.37-7.26 (m, 4H), 7.19-7.16 (m,2H), 6.83 (d, J = 7.99 Hz, 1H), 4.79 (t, J = 6.79 Hz, 1H,), 1.36 (d, J =6.79 Hz, 3H), 1.2 (s, 1H)  1  6

(S)-1-(1-(3- chlorophenyl)- 2-hydroxyethyl)- 3-(1-(2-(cyclo-propyl-amino) pyrimidin-4-yl)- 1H-pyrazol- 4-yl)urea 1HNMR (400 MHz,DMSO-d₆): δ 8.64 (s, 1H), 8.51 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.73(s, 1H), 7.50 (br s, 1H), 7.35-7.31 (m, 2H), 7.27-7.25 (m, 2H), 6.97 (d,J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 5.015-4.94 (m, 1H), 4.73-4.71 (m,1H), 3.64-3.58 (m, 2H), 2.73-2.72 (m, 1H), 0.67-0.66  1 (m, 2H), 0.47(s, 2H)  7

(S)-1-(1-(2-((2- chlorophenyl) amino) pyrimidin-4- yl)-1H-pyrazol-4-yl)- 3-(2-hydroxy- 1-phenylethyl) urea 1HNMR (400 MHz,DMSO-d₆): δ 9.01 (s, 1H), 8.63 (s, 1H), 8.39 (d, J = 5.59 Hz, 2H), 7.78(s, 1H), 7.74 (d, J = 3.04 Hz, 1H), 7.49 (d, J = 7.99 Hz, 1H), 7.34-7.29 (m, 4H), 7.22- 7.15 (m, 3H), 6.73 (d, J = 7.6 Hz, 1H), 4.91 (br s,1H), 4.73-7.71 (m, 1H), 3.63-3.56 (m, 2H)  1  9

1-(3-chloro- benzyl)-3-(1- (2-((2-chloro- phenyl)amino) pyrimidin-4-yl)-1H- pyrazol-4-yl) urea 1HNMR (400 MHz, DMSO-d₆): δ 9.04 (s, 1H),8.71 (s, 1H), 8.43 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.80 (s, 1H), 7.75(d, J = 8 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.35-7.23 (m, 5H),7.20-7.16 (m, 2H), 6.85 (br s, 1H), 4.28 (d, J = 5.6 Hz, 2H)  1  10

(R)-1-(1-(2- (2-chloro- phenyl)amino) pyrimidin-4- yl)-1H-pyrazol-4-yl)- 3-(1-(3-chloro- phenyl)ethyl) urea 1HNMR (400 MHz,DMSO-d₆): δ 9.02 (s, 1H), 8.45 (s, 1H), 8.39 (t, J = 5.2 Hz, 2H), 7.79(s, 1H), 7.74 (d, J = 8 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 7.37-7.26 (m,5H), 7.19-7.15 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H), 4.79 (t, J = 7.2 Hz,1H), 1.36 (d, J = 6.8 Hz, 3H)  1  11

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3-(1-(2- ((2-chloro-phenyl)amino) pyrimidin-4- yl)-5- methyl-1H- pyrazol-4-yl) urea 1HNMR(400 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.47 (s, 1H), 8.33 (d, J = 4.8 Hz,2H), 7.73 (d, J = 8 Hz, 1H), 7.47 (d, J = 8 Hz, 1H), 7.34- 7.26 (m, 5H),7.19- 7.09 (m, 2H), 6.94 (d, J = 7.6 Hz, 1H), 5.01 (s, 1H), 4.73- 4.70(m, 1H), 3.65- 3.61 (m, 2H), 2.22 (s, 3H)  1  12

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-(phenyl- amino)pyrimidin-4- yl)-1H- pyrazol-4-yl) urea 1HNMR (400 MHz, DMSO-d₆): δ 9.73(s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.79 (s,1H), 7.73 (d, J = 8 Hz, 2H), 7.36-7.32 (m, 2H), 7.29-7.15 (m, 4H), 7.17(d, J = 5.6 Hz, 1H), 6.96 (t, J = 6.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H),4.9 (br s, 1H), 4.75- 4.73 (m, 1H), 3.65-  1 3.57 (m, 2H)  13

1-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-(((R)-1-hydroxy-4- methylpentan- 2-yl)amino) pyrimidin-4- yl)-1H-pyrazol-4-yl)urea 1HNMR (400 MHz, DMSO-d₆): δ 8.63 (s, 1H), 8.48 (br s, 1H),8.23 (br s, 1H), 7.72 (s, 1H), 7.35- 7.32 (m, 2H), 7.28- 7.26 (m, 2H),6.93- 6.87 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 4.98 (t, J = 5.2 Hz, 1H),4.73-4.72 (m, 1H), 4.59 (s, 1H), 4.05 (br s, 1H), 3.65-3.55 (m, 2H),3.43-3.38 (m, 1H),  2 1.66-1.59 (m, 1H), 1.39-1.36 (m, 2H), 0.88-0.86(m, 6 H)  14

1-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-((trans-4-hydroxycyclo- hexyl)amino) pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR(400 MHz, DMSO-d₆): δ 8.64 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.20-7.66 (m, 2H), 7.53 (s, 1H), 7.35-7.23 (m, 4H), 6.91 (d, J = 5.2 Hz, 1H),6.83 (d, J = 8.4 Hz, 1H), 4.98 (s, 1H), 4.82 (s, 1H), 4.73 (s, 1H),4.59-4.52 (m, 1H), 4.49-4.40 (m, 1H), 4.12 (s, 1H), 3.71 (s, 1H),  13.61 (s, 1H), 3.49 (s, 1H), 1.99-1.90 (m, 2H), 1.35 (m, 4H)  15

(S)-1-(1-(2- ((4-(4-acetyl- piperazin-1- yl)-2-methoxy- phenyl)amino)pyrimidin-4- yl)-1H-pyrazol- 4-yl)-3-(1- (3-chloro- phenyl)-2-hydroxyethyl) urea 1HNMR (400 MHz, DMSO-d₆): δ 8.65 (s, 1H), 8.42 (s,1H), 8.34 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 7.78 (s, 1H), 7.62 (d, J =8.8 Hz, 1H), 7.36-7.27 (m, 4H), 7.05 (d, J = 4.8 Hz, 1H), 6.84 (d, J =7.6 Hz, 1H), 6.63 (s, 1H), 6.50 (d, J = 7.6 Hz, 1H), 4.98 (s, 1H), 4.74(d, J = 6 Hz, 1H), 3.79 (s, 3H), 3.58 (br s, 6H), 3.10 (d, J = 24.8 Hz,4H), 2.03 (s, 3H)  1  16

1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-(cyclo- propylamino)pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR (400 MHz, DMSO-d₆): δ 8.63(s, 1H), 8.51 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.72 (s, 1H), 7.51 (s,1H), 7.35- 7.32 (m, 2H), 7.28 (d, J = 7.6 Hz, 2H), 6.96 (t, J = 5.2 Hz,1H), 6.81 (d, J = 7.6 Hz, 1H), 4.99-4.96 (m, 1H), 4.74-4.70 (m, 1H),3.65-3.57 (m, 2H), 2.74-2.72 (m, 1H), 0.68-0.66  1 (d, J = 6.4 Hz, 2H),0.46 (s, 2H)  18

(S)-3-(1-(2- (cyclopropyl- amino) pyrimidin-4- yl)-1H-pyrazol-4-yl)-1-(2- hydroxy-1- phenylethyl)- 1-methylurea 1HNMR (400 MHz,DMSO-d₆): 8.69 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.75 (s, 1H),7.38-7.26 (m, 4H), 7.14 (d, J = 5.6 Hz, 1H), 6.66 (s, 1H), 5.55- 5.52(m, 1H), 5.34 (s, 1H), 4.68 (br s, 1H), 4.23-4.11 (m, 2H), 2.80 (s, 3H),0.87-0.83 (m, 2H), 0.57 (br s, 2H)  2  20

(S)-1-(1-(2- ((2-chloro- 4-fluoro- phenyl)amino) pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1- (3-chloro- phenyl)-2- hydroxyethyl) urea1HNMR (400 MHz, CDCl₃, few drops MeOD): 8.50 (s, 1H), 8.33 (d, J = 5.2Hz, 1H), 8.27- 8.25 (m, 1H), 7.51 (s, 1H), 7.28-7.19 (m, 1H), 7.23-7.12(m, 3H), 7.12-7.10 (m, 1H) 7.04-6.99 (m, 1H), 6.23 (d, J = 6.8 Hz, 1H)4.87-4.84 (m, 1H), 3.81-3.77 (m, 1H), 3.64-3.61 (m, 1H)  2  21

(S)-1-(1-(2- (benzo[d][1,3] dioxol-5- ylamino)- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1-(3- chlorophenyl)- 2-hydroxyethyl) urea 1HNMR(400 MHz, DMSO-d₆): δ 9.60 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.42 (d,J = 5.6 Hz, 1H), 7.78 (s, 1H), 7.41 (d, J = 2 Hz, 1H), 7.36-7.34 (m,2H), 7.32-7.27 (m, 2H), 7.13-7.09 (m, 2H), 6.83 (t, J = 6 Hz, 2H), 5.95(s, 2H), 4.99 (t, J = 4.1 Hz, 1H), 4.74-4.72 (m, 1H), 3.65-3.57 (m,  12H)  22

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-((4-(4- methyl-piperazin-1- yl)-phenyl) amino) pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea1HNMR (400 MHz, DMSO-d₆): δ 9.47 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H),8.39 (d, J = 5.6 Hz, 1H), 7.78 (s, 1H), 7.54 (d, J = 9.2 Hz, 2H), 7.34(m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 5.6 Hz, 1H), 6.89- 6.83(m, 3H), 4.99 (t, J = 5.2 Hz, 1H), 4.73 (t, J = 7.2 Hz, 1H), 3.65-3.56(m, 2H), 3.08 (br s, 3H), 2.31 (br s, 2H) (some aliphatic protons aremerged  1 with solvent signal)  23

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(5-methyl-2-(pyridin-3- yl-amino) pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR(400 MHz, DMSO-d₆): δ 9.79 (s, 1H), 8.86 (s, 1H), 8.70 (s, 1H), 8.61 (s,1H), 8.40 (s, 1H), 8.14 (d, J = 5.2 Hz, 2H), 7.80 (s, 1H), 7.34 (t, J =7.6 Hz, 2H), 7.30-7.27 (m, 3H), 6.84 (d, J = 7.6 Hz, 1H), 5.0 (t, J =4.8 Hz, 1H), 4.73 (t, J = 6.8 Hz, 1H), 3.65-3.56 (m, 2H), 2.44 (s, 3H) 2  24

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-(pyridin-3-yl-amino) pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR (400 MHz,DMSO-d₆): δ 10.08 (s, 1H), 8.98 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H),8.52 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 4.8 Hz, 2H), 7.81 (s, 1H), 7.46(d, J = 7.6 Hz, 2H), 7.36-7.32 (m, 2H), 7.29-7.25 (m, 3H), 6.87 (d, J =7.6 Hz, 1H), 4.73 (t, J = 7.2 Hz, 1H)  2  25

(S)-1-(1-(2- ((2-chloro- 4-fluoro- phenyl)amino)- 5-methyl- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)urea1HNMR (400 MHz, DMSO-d₆): δ 8.92 (s, 1H), 8.62 (s, 1H), 8.42 (s, 1H),8.27 (s, 1H), 7.79 (s, 1H), 7.70-7.66 (m, 1H), 7.48-7.45 (m, 1H),7.35-7.32 (m, 2H), 7.28-7.26 (m, 2H), 7.20-7.17 (m, 1H), 6.79 (d, J =7.2 Hz, 1H), 4.98 (s, 1H), 4.74-4.72 (m, 1H), 3.64-3.56 (m, 2H), 2.40(s, 3H)  2  26

(S)-1-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-((2-chloro-4- fluorophenyl) amino)-5- methyl- pyrimidin-4- yl)-1H-pyrazol-4-yl)urea 1HNMR (400 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.62 (s, 1H), 8.41(s, 1H), 8.27 (s, 1H), 7.79 (s, 1H), 7.70-7.66 (m, 1H), 7.50-7.46 (m,2H), 7.32-7.31 (m, 2H), 7.20-717 (m, 1H), 6.79 (d, J = 8 Hz, 1H), 4.98(t, J = 4.8 Hz, 1H), 4.73-4.71 (m, 1H), 3.62-3.57 (m, 2H), 2.40 (s, 3H) 2  27

(S)-1-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-((2-chloro-phenyl) amino)-5- methyl- pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea1HNMR (400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H),8.31 (s, 1H), 7.80 (d, J = 4.4 Hz, 2H), 7.48 (t, J = 6 Hz, 2H),7.37-7.27 (m, 3H), 7.15-7.12 (m, 1H), 6.79 (d, J = 8 Hz, 1H), 4.98 (t, J= 5.2 Hz, 1H), 4.74- 4.72 (m, 1 Hz), 3.63-3.55 (m, 2H), 2.48 (s, 3H)  2 28

1-(1-(3-chloro- phenyl)-2- hydroxy- ethyl)-3-(1-(2- (cyclopropyl-amino)-5- methyl- pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR (400 MHz,DMSO-d₆): δ 8.60 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.72 (s, 1H),7.34-7.25 (m, 5H), 6.77 (d, J = 7.2 Hz, 1H), 4.97 (t, J = 7.2 Hz, 1H),4.72 (d, J = 6.8 Hz, 1H), 3.63- 3.54 (m, 2H), 2.67- 2.64 (m, 1H), 2.34(s, 3H), 0.64-0.62 (m, 2H), 0.43 (br s, 2H)  2  29

(S)-1-(2-((2- chloro-4- fluorophenyl)- amino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.37 (s, 1H), 8.25 (d, J = 8.4Hz, 1H), 7.95 (s, 1H), 7.69-7.65 (m, 1H), 7.49-7.41 (m, 1H), 7.37-7.18(m, 6H), 6.75 (s, 1H), 5.04- 4.99 (m, 1H), 4.92 (br s, 1H), 3.65-3.64(m, 2H), 2.28 (s, 3H).  3  30

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-(cyclo-propyl-amino)- 5-fluoro- pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR(400 MHz, DMSO-d₆): δ 8.68 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 7.79 (s,1H), 7.57 (s, 1H), 7.35-7.32 (m, 2H), 7.28 (br s, 2H), 6.84 (d, J = 7.2Hz, 1H), 4.98 (s, 1H), 4.73 (s, 1H), 3.60 (t, J = 4.8 Hz, 2H), 1.34 (s,1H), 0.65 (d, J = 6 Hz, 2H), 0.45 (s, 2H)  1  31

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.38 (s, 1H), 8.25 (d, J = 8.4Hz, 1H), 7.69 (s, 1H), 7.69-7.65 (m, 1H), 7.49-7.41 (m, 1H), 7.37-7.18(m, 6H), 6.75 (s, 1H), 5.04- 4.99 (m, 1H), 4.92 (t, J = 5.6 Hz, 1H),3.66-3.62 (m, 2H), 2.28 (s, 3H)  3  32

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.38 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H),7.95 (s, 1H), 7.68 (br s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.35 (d, J =8.4 Hz, 3H), 7.31-7.21 (m, 4H), 6.76 (s, 1H), 5.04 (s, 1H), 4.86 (br s,1H), 3.64 (s, 2H), 2.29 (s, 3H)  3  33

1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-(phenyl- amino)-pyridin-4-yl)- 1H-pyrazol- 4-yl)urea 1HNMR (400 MHz, DMSO-d₆): δ 9.08(s, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.72 (s,1H), 7.64 (d, J = 8 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.28-7.22 (m,4H), 7.19 (s, 1H), 7.10 (d, J = 4.4 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H),6.83 (d, J = 8 Hz, 1H), 4.98 (t, J = 5.2 Hz, 1H),  7, 1 4.73 (d, J = 7.6Hz, 1H), 3.66-3.56 (m, 2H)  34

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-(phenyl- amino)pyridin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR (400 MHz, DMSO-d₆): δ 9.08(s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.72 (s,1H), 7.64 (d, J = 8 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.28-7.22 (m,4H), 7.19 (s, 1H), 7.10 (d, J = 4.4 Hz, 1H), 6.89-6.82 (m, 2H), 4.99 (brs, 1H), 4.74-4.72 (m, 1H), 3.63-3.58 (m,  7, 1 2H)  35

(S)-1-(2-((2- chloro-4- fluoro-phenyl) amino)-5- methyl- pyrimidin-4-yl)-N-(1- (3-chloro- phenyl)-2- hydroxy- ethyl)-1H- pyrazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.03 (s, 1H), 8.92 (s, 1H), 8.64(d, J = 8.4 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.73- 7.7.66 (m, 1H),7.50-7.47 (m, 1H), 7.43 (s, 1H), 7.35- 7.28 (m, 3H), 7.25- 7.20 (m, 1H),5.06- 5.01 (m, 1H), 4.96 (t, J = 5.6 Hz, 1H),  3 3.66-3.61 (m, 2H), 2.48(s, 3H)  36

1-(1-(2-((2- chloro-4- fluorophenyl)- amino)-5- methyl- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)urea1HNMR (400 MHz, DMSO-d₆): δ 8.9 (s, 1H), 8.61 (s, 1H), 8.41 (s, 1H),8.27 (s, 1H), 7.78 (s, 1H), 7.68-7.65 (m, 1H), 7.46-7.44 (m, 2H),7.35-7.27 (m, 2H), 7.21-7.20 (m, 1H), 7.19-7.16 (m, 1H), 6.78 (d, J = 8Hz, 1H), 4.97 (t, J = 4.8 Hz, 1H), 4.74-4.70 (m, 1H), 3.65-3.55 (m, 2H),2.39 (s,  2 3H)  37

1-(1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)urea1HNMR (400 MHz, DMSO-d₆): δ 9.44 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H),8.32 (s, 1H), 7.78 (s, 1H), 7.37-7.32 (m, 3H), 7.28-7.26 (m, 2H), 7.11(d, J = 7.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 5.93 (s, 2H), 4.99 (t, J= 5.6 Hz, 1H), 4.73- 4.722 (m, 1H), 3.63- 3.58 (m, 2H), 2.4 (s, 3H)  2 38

(S)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-((3- ethynyl-phenyl)amino) pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR (400 MHz,DMSO-d₆): δ 9.85 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 7.87 (s, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.36-7.26 (m, 5H), 7.20(d, J = 5.6 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H),4.99 (t, J = 4.8 Hz, 1H), 4.73 (d, J = 6.4 Hz, 1H), 4.06  2 (s, 1H),3.64-3.57 (m, 2H)  39

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (cyclopropyl-amino)-5- methyl- pyrimidin-4- yl)-1H- pyrazole-4- carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 9.00 (s, 1H), 8.61 (d, J = 8 Hz, 1H), 8.32 (s,1H), 8.22 (s, 1H), 7.44 (d, J = 11.2 Hz, 2H), 7.36-7.27 (m, 3H),5.07-5.01 (m, 1H), 4.98-4.95 (m, 1H), 3.66-3.65 (m, 2H), 2.76-2.73  3(m, 1H), 2.34 (s, 3H), 0.68 (d, J = 5.2 Hz, 2H), 0.48 (d, J = 2.4 Hz,2H)  40

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (cyclopropyl- amino)-5-methyl- pyrimidin-4- yl)-1H- pyrazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.99 (s, 1H), 8.61 (d, J = 8 Hz, 1H), 8.32 (s, 1H), 8.22 (s,1H), 7.44 (d, J = 10.3 Hz, 2H), 7.31 (d, J = 13.6 Hz, 3H), 5.04-4.90 (m,1H), 4.95 (d, J = 5.2 Hz, 1H), 3.65 (s, 2H),  3 2.65 (br s, 1H), 2.36(s, 3H), 0.68 (d, J = 4.8 Hz, 2H), 0.47 (br s, 2H)  41

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1H- pyrazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.58 (s, 1H), 9.02 (s, 1H), 8.66(d, J = 8.0 Hz, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.44 (s, 1H), 7.37-7.30(m, 4H), 7.12 (d, J = 9.6 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.95 (s,2H), 5.06-5.04 (m, 1H), 4.96 (br s, 1H),  3 3.65 (br s, 2H), 2.40 (s,3H)  42

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.53 (s, 1H), 8.43 (s, 1H), 8.26(d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.32 (s,2H), 7.28 (br s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.83-6.78 (m, 2H), 5.94(s, 2H), 5.04- 5.01 (m, 1H), 4.92 (t, J = 5.2 Hz, 1H),  3 3.63 (d, J =4.8 Hz, 2H), 2.29 (s, 3H)  43

1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-((2- chloro-phenyl)amino)-5- methyl- pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR (400 MHz,DMSO-d₆): δ 8.78 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 7.79(t, J = 3.6 Hz, 2H), 7.47 (d, J = 8 Hz, 1H), 7.39-7.25 (m, 4H), 7.13 (t,J = 6.7 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.73(br s, 1H), 3.65-3.55 (m, 2H), 2.47 (s, 3H)  2  44

(S)-1-(1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)urea1HNMR (400 MHz, DMSO-d₆): δ 9.44 (s, 1H), 8.66 (s, 1H), 8.57 (s, 1H),8.32 (s, 1H), 7.78 (s, 1H), 7.37-7.32 (m, 3H), 7.27 (d, J = 7.2 Hz, 2H),7.12-7.09 (m, 1H), 6.8-6.79 (m, 2H), 5.94 (s, 2H), 5.0 (t, J = 4.8 Hz,1H), 4.74 (t, J = 5.2 Hz, 1H), 3.65-3.57 (m, 2H), 2.4 (s, 3H)  2  45

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.04 (s, 1H), 8.93 (s, 1H), 8.64(d, J = 8.4 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.73- 7.50 (m, 1H),7.49- 7.43 (m, 1H), 7.35 (s, 1H), 7.33-7.28 (m, 3H), 7.25-7.20 (m, 1H),5.06-5.01 (m, 1H), 4.97-4.94 (m, 1H), 3.65 (t,  3 J = 6.4 Hz, 2H), 2.40(s, 3H)  46

N-(1-(3-chloro- phenyl)-2- hydroxy- ethyl)-1-(2- (phenyl-amino)pyridin-4- yl)-1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.13 (s, 1H), 8.35-8.1 (m, 2H), 8.0-7.9 (m, 1H), 7.8-7.55 (m, 2H),7.5-7.11 (m, 7H), 7.11-6.71 (m, 4H), 5.1-4.90 (m, 2H), 3.65 (br s, 2H) 7  47

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.53 (s, 1H), 8.42 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H),8.0 (s, 1H), 7.41 (s, 2H), 7.37 (d, J = 6.8 Hz, 2H), 7.28 (t, J = 7.2Hz, 1H), 7.21 (d, J = 6.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.83-6.79(m, 2H), 5.94 (s, 2H), 5.04  3 (d, J = 7.6 Hz, 1H), 4.86 (br s, 1H),3.65 (br s, 2H), 2.29 (s, 3H)  48

(S)-1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): 9.65 (s, 1H), 8.51 (s, 1H), 8.41(d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.43 (s, 1H), 7.38 (s,1H), 7.34-7.32 (m, 3H), 7.06 (d, J = 1.6 Hz, 1H), 6.82 (d, J = 8.4 Hz,1H), 5.94 (s, 2H), 5.03 (br s, 2H), 3.73-3.71 (m, 2H), 2.25 (s, 3H)  6 49

(R)-1-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-3-(1-(2- (phenylamino)pyridin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR (400 MHz, DMSO-d₆): δ 9.08(s, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.72 (s,1H), 7.64 (d, J = 8 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.28-7.10 (m,6H), 7.19 (s, 1H), 7.10 (d, J = 4.4 Hz, 1H), 6.88-6.82 (m, 2H), 4.98 (t,J = 5.2 Hz, 1H), 4.73 (br s, 1H), 3.65-3.55 (m, 2H)  7, 1  50

(S)-1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1H- pyrazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.58 (s, 1H), 9.01 (s, 1H), 8.65(d, J = 8.0 Hz, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.44 (s, 1H), 7.37-7.30(m, 4H), 7.12 (d, J = 6.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.95 (s,2H), 5.08-5.02 (m, 1H), 4.96 (t, J = 5.2 Hz,  3 1H), 3.65 (br s, 2H),2.40 (s, 3H)  51

(R)-1-(1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)urea1HNMR (400 MHz, DMSO-d₆): δ 9.44 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H),8.32 (s, 1H), 7.78 (s, 1H), 7.36-7.32 (m, 3H), 7.29-7.26 (m, 2H),7.11-7.09 (m, 1H), 6.82-6.79 (m, 2H), 5.94 (s, 2H), 4.99 (t, J = 5.2 Hz,1H), 4.74-4.72 (m, 1H), 3.65-3.57 (m, 2H), 2.47 (s, 3H)  2  52

N-(1-(3-chloro- phenyl)-2- hydroxy- ethyl)-1-(2- (phenyl-amino)pyrimidin-4- yl)-1H- pyrazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.85 (s, 1H), 9.04 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.59 (d, J = 5.6 Hz,1H), 8.29 (s, 1H), 7.75 (d, J = 8 Hz, 2H), 7.45 (s, 1H), 7.34-7.27 (m,6H), 7.00-6.90 (m, 1H), 5.1-4.9 (m,  3 2H), 3.67-3.65 (m, 2H)  53

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (phenylamino)pyrimidin-4- yl)-1H- pyrazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.85 (s, 1H), 9.04 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.59 (d, J = 5.6 Hz,1H), 8.29 (s, 1H), 7.75 (d, J = 8 Hz, 2H), 7.45 (s, 1H), 7.35-7.27 (m,6H), 7.02-6.98 (m, 1H), 5.05-5.02 (m,  3 1H), 4.98 (t, J = 2 Hz, 1H),3.67 (t, J = 5.2 Hz, 2H)  54

N-(2-amino-1- phenylethyl)- 1-(2-((2- chloro-4- fluoro-phenyl) amino)-5-methyl- pyrimidin-4- yl)-1H- pyrazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): 9.04 (s, 1H), 8.92 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.42 (s,1H), 8.24 (s, 1H), 7.73- 7.66 (m, 1H), 7.50- 7.47 (m, 1H), 7.34- 7.25(m, 4H), 7.24- 7.20 (m, 2H), 4.93- 4.90 (m, 1H), 2.85- 2.83 (d, J = 6.8Hz, 2H), 2.40 (s, 3H)  4  55

(S)-1-(1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(2- hydroxy-1- phenylethyl) urea 1HNMR (400 MHz,DMSO-d₆): δ 9.44 (s, 1H), 8.81 (s, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 7.77(s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.31-7.29 (m, 4H), 7.23-7.19 (m, 1H)7.12-7.09 (m, 1H), 6.9 (d, J = 7.6 Hz, 1H), 6.8 (d, J = 8 Hz, 1H), 5.97(s, 2H), 4.95 (s, 1H), 4.74-4.69 (m, 1H),  2 3.63-3.55 (m, 2H), 2.45 (s,3H)  56

(R)-1-(1-(2- ((2-chloro- 4-fluoro- phenyl)amino)- 5-methyl- pyrimidin-4-yl)-1H-pyrazol- 4-yl)-3-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)urea1HNMR (400 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.64 (s, 1H), 8.41 (s, 1H),8.27 (s, 1H), 7.79 (s, 1H), 7.70-7.60 (m, 1H), 7.47-7.45 (m, 1H),7.35-7.32 (m, 2H), 7.22 (d, J = 4 Hz, 2H), 7.19-7.17 (m, 1H), 6.8 (d, J= 8 Hz, 1H), 4.98 (t, J = 4.8 Hz, 1H), 4.73-4.72 (m, 1H), 3.64-3.65 (m,2H), 2.40 (s, 3H)  2  57

(S)-1-(2-((2- chloro-4- fluorophenyl)- amino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.38 (s, 1H), 8.27 (d, J = 8.0Hz, 1H), 7.96 (s, 1H), 7.70-7.66 (m, 1H), 7.47-7.19 (m, 7H), 6.75 (s,1H), 5.03- 5.01 (m, 1H), 3.64 (br s, 2H), 2.29 (s, 3H)  3  58

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(3,5- dichloro- phenyl)-2- hydroxy- ethyl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.43 (s, 1H), 8.29(d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.46-7.40 (m, 5H), 7.11 (d, J = 8.4Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 5.94 (s, 2H), 5.04-4.98(m, 2H), 3.66-3.65 (m, 2H), 2.29 (s, 3H)  3  59

(S)-1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1- hydroxy-3- phenyl- propan-2- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 9.52 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H),7.73 (d, J = 8.8 Hz, 1H), 7.39-7.38 (m, 2H), 7.24-7.23 (m, 4H),7.13-7.09 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.70 (s, 1H), 5.94 (s, 2H),4.78 (t, J = 5.2 Hz, 1H), 4.11 (s, 1H), 3.46 (t, J = 6 Hz, 1H),3.40-3.37 (m, 1H), 2.95-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.28 (s, 3H)  3 60

(S)-1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.43 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H),8.01 (s, 1H), 7.46-7.40 (m, 6H), 7.11 (d, J = 8.4 Hz, 1H), 6.83-6.81 (m,2H), 6.77 (s, 1H), 5.94 (s, 2H), 5.04- 4.98 (m, 2H), 3.66 (d, J = 7.2Hz, 2H), 2.29 (s, 3H)  3  61

(R)-1-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-3- (1-(2-((2- chloro-phenyl)amino)- 5-methyl- pyrimidin-4- yl)-1H-pyrazol- 4-yl)urea 1HNMR(400 MHz, DMSO-d₆): δ 8.78 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.30 (s,1H), 7.80 (d, J = 4.0 Hz, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.35-7.31 (m,3H), 7.28-7.26 (m, 2H), 7.13 (t, J = 8.8 Hz, 1H), 6.83 (d, J = 7.60 Hz,1H), 4.98 (t, J = 5.2 Hz, 1H), 4.73 (d, J = 7.2 Hz, 1H), 3.63-3.58 (m, 2 2H), 2.48 (s, 3H)  62

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (2-((2,2- difluoro-benzo[d][1,3] dioxol-5- yl)amino)-5- methyl- pyrimidin-4- yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.90 (s, 1H), 8.49(s, 1H), 8.28 (d, J = 8 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H),7.45-7.39 (m, 3H), 7.36-7.27 (m, 4H), 6.79 (d, J = 1.2 Hz, 1H), 5.06-5.03 (m, 1H), 4.93 (t, J = 5.6 Hz, 1H), 3.68-3.64 (m, 2H), 2.32 (s, 3H) 3  63

1-(2-((2,2- difluoro- benzo[d][1,3] dioxol-5- yl)amino)-5- methyl-pyrimidin-4- yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.89 (s, 1H), 8.49 (s, 1H), 8.24(d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 7.40-7.38(m, 3H), 7.36-7.31 (m, 3H), 7.21-7.19 (m, 1H), 6.80 (s, 1H), 5.07-5.02(m, 1H), 4.86 (t, J = 5.2 Hz, 1H), 3.65 (s, 2H), 2.32 (s, 3H)  3  64

(S)-1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(2- methoxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.42 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H),8.01 (s, 1H), 7.41-7.38 (m, 4H), 7.31-7.29 (m, 2H), 7.25-7.21 (m, 1H),7.11-7.09 (m, 1H), 6.83-6.81 (m, 2H), 5.94 (s, 2H), 5.28- 5.22 (m, 1H),3.65 (t, J = 10 Hz, 1H),  3 3.56-3.54 (m, 1H), 2.29 (s, 3H)  65

1-(2-(benzo- furan-5- ylamino)-5- methyl- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 9.65 (s, 1H), 8.45 (s, 1H), 8.24 (d, J = 8 Hz, 1H),8.08-8.06 (m, 2H), 7.91 (d, J = 2 Hz, 1H), 7.54 (s, 1H), 7.52-7.45 (m,2H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 2H), 7.30-7.28 (m, 2H), 6.90 (d, J= 2.0 Hz, 1H), 6.78  3 (s, 1H), 5.08-5.04 (m, 1H), 4.86 (t, J = 6.0 Hz,1H), 3.68-3.65 (m, 2H), 2.31 (s, 3H)  66

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- fluoro- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.67 (s, 1H), 8.63 (d, J = 4.0 Hz, 1H), 8.39 (d, J =8.0 Hz, 1H), 8.18 (s, 1H) 7.57 (s, 1H), 7.37-7.30 (m, 5H), 7.22-7.19 (m,1H), 7.08 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 6.84 (s, 1H), 5.96 (s, 2H),5.03 (d, J = 6.8 Hz, 1H), 4.87  3 (s, 1H), 3.65 (d, J = 6.8 Hz, 2H)  67

1-(2-((2- chloro-phenyl) amino)-5- fluoro- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 9.15 (s, 1H), 8.61 (d, J = 4.0 Hz, 1H), 8.38 (d, J = 7.6 Hz,1H), 8.13 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51 (s 2H), 7.35- 7.34 (m,3H), 7.29 (t, J = 8.0 Hz, 2H), 7.22-7.17 (m, 2H), 6.83 (d, J = 1.6 Hz, 3 1H), 5.05-5.00 (m, 1H), 4.86 (t, J = 6 Hz, 1H), 3.69-3.61 (m, 2H). 68

1-(2-(benzo- furan-5- ylamino)-5- methyl- pyrimidin-4- yl)-N-(1-(3-chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.46 (s, 1H), 8.29 (d, J = 8.00 Hz, 1H),8.07 (d, J = 7.2 Hz, 2H), 7.91 (d, J = 2.0 Hz, 1H), 7.54- 7.47 (m, 4H),7.43 (s, 2H), 7.33 (s, 1H), 7.29 (s, 1H), 6.89 (s, 1H), 6.77 (s, 1H),5.07-5.04 (m, 1H), 4.93 (t, J = 6.0 Hz, 1H), 3.66  3 (d, J = 4.0 Hz,2H), 2.31 (s, 3H)  69

(S)-N-(1-(3-chloro- 4-fluoro- phenyl)-2- hydroxy- ethyl)-1-(2-((2,2-difluoro- benzo[d][1,3] dioxol-5-yl) amino)-5- methyl-pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.90 (s, 1H), 8.49 (s, 1H), 8.27 (d, J = 8 Hz, 1H), 8.03 (s, 1H), 7.91(s, 1H), 7.56- 7.46 (m, 1H), 7.44- 7.41 (m, 1H), 7.40- 7.29 (m, 4H),6.79- 6.78 (m, 1H), 5.07- 5.01 (m, 1H), 4.93 (t, J = 5.6 Hz, 1H),3.67-3.64 (m, 2H), 2.32 (s, 3H)  3  70

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chloro-2- fluorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.43 (s, 1H), 8.34(d, J = 6.8 Hz, 1H), 8.01 (s, 1H), 7.44-7.41 (m, 4H), 7.19 (t, J = 7.6Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.77 (s,1H), 5.94 (s, 2H), 5.33 (d, J = 6.4 Hz, 1H), 5.03 (s, 1H), 3.66 (d, J =5.2 Hz,  3 2H), 2.29 (s, 3H)  71

N-(2- hydroxy-1- phenylethyl)- 1-(2- (phenylamino) pyridin-4-yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.18(t, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.65 (d, J = 8 Hz, 2H), 7.43 (s, 1H),7.37-7.32 (m, 2H), 7.26-7.19 (m, 5H), 7.04-7.03 (m, 1H), 6.95 (s, 1H),6.90 (t, J = 8  7 Hz, 1H), 6.78 (s, 1H), 5.07-5.01 (m, 1H), 4.86 (t, J =5.2 Hz, 1H), 3.70- 306 (m, 2H)  72

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (phenylamino)pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.18 (s, 1H), 8.45 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 7.2Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H) 7.42 (s, 1H), 7.32-7.28 (m, 2H),7.27-7.25 (m, 3H), 7.16 (d, J = 5.6 Hz, 1H), 13 7.02 (s, 1H), 6.91 (t, J= 6.8 Hz, 1H), 5.03-4.99 (m, 2H), 3.73 (t, J = 5.6 Hz, 2H)  73

N-(2- hydroxy-1- phenylethyl)- 1-(5-methyl- 2-((4- (piperazin-1-yl)-phenyl) amino) pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 9.43 (s, 1H), 8.40 (s, 1H), 8.25 (d, J = 8.4 Hz,1H), 8.01 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.37-7.31 (m,2H), 7.30-7.28 (m, 2 H), 7.21-7.19 (m, 1H), 6.89 (d, J = 8.8 Hz, 2H),6.79 (s, 1H), 5.03 (t, J = 7.2 Hz, 1H), 4.88 (s, 1H), 3.65 (br s, 2H),3.10-3.02 (m, 8H), 2.29 (s, 3H)  3  74

N-(2- hydroxy-1- phenylethyl)- 1-(5-methyl- 2-(phenyl- amino)pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): 9.04(s, 1H), 8.13 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.61 (d,J = 8 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H) 7.29-7.22 (m, 5H), 7.19-7.08 (m,1H), 6.87 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6 Hz,  8 2H), 5.06-5.01(m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 3.66- 3.63 (m, 2H), 2.14 (s, 3H)  75

N-(2- hydroxy-1- phenylethyl)- 1-(2-(((S)-1- hydroxy- butan-2-yl)amino)-5- methyl- pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR (400 MHz,DMSO-d₆): δ 8.23 (s, 2H), 7.94 (s, 1H), 7.35 (d, J = 8.0 Hz, 3H), 7.29(t, J = 7.2 Hz, 2H), 7.21 (d, J = 7.2 Hz, 1H), 6.77 (t, J = 8.4 Hz, 2H),5.03 (d, J = 6.0 Hz, 1H), 4.90 (s, 1H), 4.56 (s,  3 carboxamide 1H),3.81 (s, 1H), 3.64 (s, 2H), 3.32 (br s, 1H), 2.21 (s, 3H), 1.64 (br s,2H), 1.45-1.41 (m, 1H), 0.85 (t, J = 6.8 Hz, 3H)  76

1-(2- (benzo[d][1,3] dioxol-5- ylamino) pyridin-4-yl)- N-(2-hydroxy-1-phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ8.99 (s, 1H), 8.18-8.14 (m, 2H), 8.00 (s, 1H), 7.40 (s, 2H), 7.37-7.31(m, 2H), 7.30-7.22 (m, 2H), 7.21-7.19 (m, 2H), 6.99-6.94 (m, 2H),6.84-6.77 (m, 3H), 5.94 (s, 2H), 5.06- 5.01 (m, 1H), 4.86 (s, 1H), 3.50(d, J = 5.6 Hz, 2H)  7  77

N-(1-(3-chloro- phenyl)-2- hydroxy- ethyl)-1-(2- (phenyl- amino)pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.17 (s, 1H), 8.45 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 7.6Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.42 (s, 1H), 7.32- 7.28 (m, 2H),7.27- 7.25 (m, 3H), 7.15 (d, J = 5.6 Hz, 1H),  7 7.02 (s, 1H), 6.92 (t,J = 7.2 Hz, 1H), 5.04-4.99 (m, 2H), 3.73 (t, J = 5.6 Hz, 2H)  78

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyridin-4-yl)-N-(2-hydroxy- 1-phenylethyl)- 1H-pyrrole-3- carboxamide 1HNMR (400 MHz,DMSO-d₆): 8.45 (s, 1H), 8.12 (s, 1H), 8.10 (d, J = 6.4 Hz, 2H),7.99-7.95 (m, 1H), 7.67 (s, 1H), 7.46-7.43 (m, 1H), 7.37 (d, J = 7.6 Hz,2H), 7.33 (t, J = 7.6 Hz, 2H), 7.24-7.16 (m, 2H), 7.09 (s, 1H), 6.76 (s,1H), 5.08-5.02 (m, 1H), 4.88 (t, J = 6.0 Hz,  8 1H), 3.66 (s, 2H), 2.16(s, 3H)  79

1-(2-(benzo- furan-5- ylamino)-5- methyl- pyridin-4-yl)- N-(2-hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): 9.02 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.05 (s,1H), 7.91 (d, J = 2 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J = 9.2 Hz, 1H),7.38 (d, J = 7.2 Hz, 3H), 7.33 (t, J = 7.6 Hz, 2H), 7.24-7.20 (m, 1H),7.10 (s, 1H), 6.91 (s, 1H), 6.76 (s,  8 1H), 6.72 (s, 1H), 5.08-5.04 (m,1H), 4.88 (t, J = 5.6 Hz, 1H), 3.66 (s, 2H), 2.16 (s, 3H)  80

1-(2-((2,2- difluorobenzo [d][1,3]dioxol- 5-yl)-amino)- 5-methyl-pyridin-4-yl)- N-(2- hydroxy-1- phenyl-ethyl)- 1H-pyrrole- 3-carboxamide1HNMR (400 MHz, DMSO-d₆): δ 9.30 (s, 1H), 8.17 (s, 1H), 8.11 (d, J = 7.6Hz, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.33-7.30(m, 3H), 7.28-7.22 (m, 2H), 7.11 (s, 1H), 6.77 (s, 1H), 6.72 (s, 1H),5.08-5.03 (m, 1H), 4.87 (t, J = 5.6 Hz, 1H), 3.66-3.65 (m, 2H), 2.17 (s,3H)  8  81

N-(2- hydroxy-1- phenylethyl)- 1-(5-methyl- 2-(pyridin-3- ylamino)pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.29 (s, 1H), 8.77 (s, 1H), 8.19-8.10 (m, 4H), 7.69 (s, 1H), 7.38 (d, J= 7.2 Hz, 2H), 7.33-7.29 (m, 3H), 7.28-7.27 (m, 1H), 7.20 (s, 1H), 6.77(s, 2H), 5.07-5.05 (m, 1H), 4.87 (s,  8 1H), 3.66 (s, 2H), 2.18 (s, 3H). 82

1-(2-((2- chloro-4- fluorophenyl) amino) pyridin-4-yl)- N-(2- hydroxy-1-phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.13(d, J = 7.2 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J = 7.2 Hz, 1H), 8.13 (d, J= 8.0 Hz, 1H), 7.86 (s, 1H), 7.79-7.77 (m, 1H), 7.76 (s, 1H), 7.48 (d, J= 7.6 Hz, 1H), 7.39-7.37 (m, 2H), 7.34-7.31 (m, 4H), 7.23 (t, J =  7 7.6Hz, 1H), 6.82 (s, 1H), 5.07-5.03 (m, 1H), 4.89 (t, J = 5.6 Hz, 1H), 3.67(t, J = 6.0 Hz, 2H).  83

N-(2- hydroxy-1- phenylethyl)- 1-(5-methyl- 2-((4- (piperazin-1-yl)-phenyl) amino)- pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): 8.76 (s, 1H), 8.09 (d, J = 14.0 Hz, 2H), 7.64 (s, 1H),7.44 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz,2H), 7.24 (d, J = 6.8 Hz, 1H), 7.07 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H),6.75 (s, 1H), 6.24 (s, 1H), 5.06-5.04 (m, 1H), 4.87 (s, 1H), 3.65 (s,2H), 2.99 (s, 4H), 2.89 (s, 4H), 2.13 (s, 3H)  3a  84

1-(2-((4- fluoro-phenyl) amino) pyridin-4-yl)- N-(2- hydroxy-1-phenyl-ethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.15 (s, 1H), 8.17 (d, J = 6.0 Hz, 2H), 8.01 (s, 1H), 7.67-7.64 (m, 2H),7.42 (s, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 14.0 Hz, 3H), 7.21(t, J = 7.6 Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 7.02 (d, J = 4.0 Hz, 1H),6.89 (s,  7 1H), 6.71 (s, 1H), 5.06-5.01 (m, 1H), 4.87-4.80 (m, 1H),3.69-3.63 (m, 2H).  85

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyridin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.51 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 11.6Hz, 2H), 7.96 (s, 1H), 7.92-7.88 (m, 1H), 7.45-7.42 (m, 1H), 7.36 (d, J= 7.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.23-7.15 (m, 2H), 6.91 (s,1H), 5.03- 11 4.96 (m, 2H), 3.71 (d, J = 5.6 Hz, 2H), 2.09 (s, 3H)  86

1-(2-((2,2- difluoro- benzo[d][1,3] dioxol-5- yl)-amino)- 5-methyl-pyridin-4-yl)- N-(2- hydroxy-1- phenyl- ethyl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 8.25 (d, J = 8.4Hz, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 1.6 Hz,1H), 7.37-7.32 (m, 2H), 7.29-7.27 (m, 3H), 7.23-7.21 (m, 2H), 6.75 (s,1H), 5.01-4.96 (m, 2H), 3.71 (d, J = 4.8 Hz, 2H), 2.10 (s, 3H) 11  87

(S)-1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.43 (s, 1H), 8.25(d, J = 8 Hz, 1H), 8.00 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.42-7.34 (m,4H), 7.20 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H),5.94 (s, 2H), 5.03 (d, J = 6.4 Hz,  3 1H), 4.93 (s, 1H), 3.65 (d, J =6.0 Hz, 2H), 2.29 (s, 3H)  88

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyridin-4-yl)-N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.13(s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.34- 7.28 (m, 4H),6.93 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 5.93(s, 2H), 5.03-5.01 (m, 11 2H), 3.72 (t, J = 5.6 Hz, 2H), 2.07 (s, 3H) 89

N-(2- hydroxy-1- phenylethyl)- 1-(5-methyl- 2-(phenyl- amino)pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.12 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.98(s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H), 7.30-7.27(m, 2H), 7.25-7.20 (m, 4H), 6.88 (t, J = 11 7.2 Hz, 1H), 6.77 (s, 1H),5.02-4.96 (m, 2H), 3.71 (d, J = 5.6 Hz, 2H), 2.09 (s, 3H).  90

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((2,2- difluoro-benzo[d][1,3] dioxol-5- yl)amino)-5- methyl- pyridin-4-yl)-1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H),8.38 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.91(s, 1H), 7.44 (s, 1H), 7.34 (d J = 4.8 Hz, 2H), 7.28 (d, J = 8.8 Hz,2H), 7.22 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 5.04-4.99 (m, 2H), 3.72 (t,J = 5.6 Hz, 2H), 11 2.10 (s, 3H)  91

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyridin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.44 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.07(s, 1H), 7.95-7.93 (m, 1H), 7.65 (s, 1H), 7.43 (t, J = 2.8 Hz, 2H),7.32-7.26 (m, 3H), 7.20-7.15 (m, 1H), 7.09 (s, 1H), 6.88 (s, 1H), 6.74(s, 1H), 5.04- 5.02 (m, 1H), 4.92  3a (t, J = 5.6 Hz, 1H), 3.65-3.62 (m,2H), 2.14 (s, 3H)  92

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((2,2- difluoro-benzo[d][1,3] dioxol-5-yl) amino)-5- methyl- pyridin-4-yl)- 1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.29 (s, 1H), 8.15 (d, J = 8Hz, 2H), 7.93 (d, J = 2 Hz, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 7.35 (d, J= 7.6 Hz, 2H), 7.28-7.26 (m, 2H), 7.22-7.20 (m, 1H), 7.10 (s, 1H), 6.75(s, 1H), 6.71 (s, 1H), 5.04-5.00 (m, 1H), 4.92 (t, J = 5.6 Hz, 1H),3.67-3.63 (m, 2H),  3a 2.15 (s, 3H)  93

N-(3-chloro- 2-(hydroxy- methyl) benzyl)-1-(5- methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.62 (t, J = 6 Hz, 1H), 8.33 (s, 1H), 8.25(s, 1H), 8.10 (s, 1H), 7.36-7.23 (m, 4H), 5.24 (t, J = 5.0 Hz, 1H), 4.76(d, J = 5.2 Hz, 2H), 4.61 (d, J = 6 Hz, 2H), 3.9 (br s, 1H), 3.83 (d, J= 11.2 Hz, 2H), 3.36 (t, J =  4, 3 11.0 Hz, 2H), 2.17 (s, 3H), 1.80 (d,J = 11.6 Hz, 2H), 1.52-1.43 (m, 2H)  94

N-(2-(2- hydroxy- ethyl) benzyl)-1- (5-methyl-2- ((tetrahydro-2H-pyran-4- yl)amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.46 (t, J = 6 Hz, 1H), 8.33 (s, 1H), 8.24(s, 1H), 8.09 (s, 1H), 7.35 (d, J = 12 Hz, 1H), 7.25 (d, J = 5.2 Hz,1H), 7.16- 7.13 (m, 3H), 4.67 (t, J = 5.2 Hz, 1H), 4.48 (d, J = 6 Hz,2H), 3.89 (br s, 1H), 3.83 (d, J =  4, 3 11.2 Hz, 2H), 3.62- 3.57 (m,2H), 3.39- 3.32 (m, 2H), 2.82 (t, J = 6.8 Hz, 2 H), 2.17 (s, 3H), 1.80(d, J = 11.2 Hz, 2H), 1.52-1.44 (m, 2H)  95

1-(2-((2,2- dimethyl- benzo[d][1,3] dioxol-5-yl)- amino)-5- methyl-pyrimidin-4- yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.41 (s, 1H),8.23 (d, J = 8 Hz, 1H), 7.99 (s, 1H), 7.41-740 (m, 1H), 7.37-7.35 (m,2H), 7.31-7.28 (m, 3H), 7.22-7.21 (m, 1H), 7.19-7.05 (m, 1H), 7.03-6.78(m, 1H), 6.72-6.70 (m, 1H), 5.05-5.03 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H),3.66 (d, J =  3 9.6 Hz, 2H), 2.28 (s, 3H), 1.6 (s, 6H)  96

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (2-((2,2- dimethyl-benzo[d][1,3] dioxol-5-yl) amino)-5- methyl- pyrimidin-4- yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.28 (s, 1H), 7.91(s, 1H), 7.37 (s, 2H), 7.33- 7.29 (m, 3H), 7.28- 7.17 (m, 1H), 6.99 (s,1H), 6.93-6.83 (m, 1H), 6.81-6.8 (m, 1H), 6.69-6.67 (m, 1H), 6.62-6.56(m, 1H), 5.25-5.23 (m, 1H), 4.0 (t, J = 5.2 Hz, 2H), 2.49 (d, J = 5.2Hz, 1H), 2.35 (s, 3H), 1.67  3 (s, 6H)  97

(R)-1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyrimidin-4-yl)-N-(2- (dimethyl- amino)-1- phenylethyl)- 1H-pyrrole- 3-carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.37 (s, 1H), 8.21 (d, J = 8.0Hz, 1H), 7.92 (s, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 6.0 Hz,1H), 7.38- 7.32 (m, 3H), 7.30 (t, J = 7.2 Hz, 2H), 7.24-7.16 (m, 2H),6.74 (s, 1H), 5.10 (br s, 1H), 2.71-  3 2.60 (m, 2H), 2.28 (s, 3H), 2.19(s, 6H)  98

N-(2-amino-1- phenylethyl)- 1-(2-((4- fluorophenyl)- amino)-5- methyl-pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.18 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.74 (s, 1H),7.66-7.63 (m, 2H), 7.37-7.29 (m, 2H), 7.22 (t, J = 6.8 Hz, 1H), 7.08 (t,J = 8.8 Hz, 3H), 6.77 (s, 1H), 6.72 (s, 1H), 5.60 (br s, 2H), 5.02 (t, J= 5.6 Hz, 1H),  9 3.02-2.89 (m, 2H), 2.14 (s, 3H)  99

N-(1-amino- 3-phenyl- propan-2- yl)-1-(2- ((2,2-difluoro- benzo[d][1,3]dioxol-5- yl)amino)-5- methyl- pyridin-4-yl)- 1H-imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 8.19 (s, 1H),8.04 (s, 1H), 7.90 (t, J = 1.6 Hz, 3 H), 7.29-7.20 (m, 6H), 7.15 (s,1H), 6.74 (s, 1H), 4.12 (s, 1H), 2.85 (d, J = 5.6 Hz, 2H), 2.65 (br s,2H), 2.09 (s, 3H)  9 100

N-(2-hydroxy- 1-phenyl- ethyl)-1-(2- (((S)-1- hydroxy- butan-2-yl)amino)-5- methyl- pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.06 (d, J = 8 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 1H),7.36-7.34 (m, 2H), 7.31-7.29 (m, 2H), 7.22-7.20 (m, 1H), 6.99 (s, 1H),6.70 (s, 1H), 6.40 (s, 1H), 6.23 (d, J = 7.6 Hz, 1H),  8 5.03-5.02 (m,1H), 4.84 (s, 1H), 4.58 (s, 1H), 3.76 (s, 1H), 3.46 (s, 2H), 3.44 (m,1H), 2.02 (s, 3H), 1.66-1.65 (m, 1H), 1.42-1.38 (m, 1H), 0.81 (t, J =12.8 Hz, 3H) 101

1-(2-((6- chloro- benzo[d][1,3] dioxol-5-yl) amino)-5- methyl-pyrimidin-4- yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H), 8.35(s, 1H), 8.26 (d, J = 8 Hz, 1H), 7.94 (s, 1H), 7.41 (s, 1H), 7.37 (s,1H), 7.33-7.30 (m, 3H), 7.21 (s, 2H), 7.10 (s, 1H), 6.75 (s, 1H), 6.06(s, 2H), 5.05-5.01 (m, 1H), 4.92-4.91 (m, 1H), 3.67-3.63  3 (m, 2H),2.27 (s, 3H) 103

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- (pyridin-3-yl) ethyl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H), 8.35 (s, 1H), 8.26 (d, J = 8Hz, 1H), 7.94 (s, 1H), 7.41 (s, 1H), 7.37 (t, J = 2.0 Hz, 1H), 7.33-7.27(m, 3H), 7.21 (s, 1H), 7.10 (s, 1H), 6.75 (d, J = 1.2 Hz, 1H), 6.05 (s,2H), 5.05-4.99 (m, 1H), 4.92 (t,  3 J = 5.6 Hz, 1H), 3.67-3.61 (m, 2H),2.27 (s, 3H) 104

1-(2- (benzo[d] oxazol-5- ylamino)-5- methyl- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 11.10 (s, 1H), 9.43 (s, 1H), 8.61 (s, 1H), 8.27 (s, 1H),8.25 (s, 1H), 8.04 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.45 (d, J = 7.2Hz, 2H), 7.32 (d, J = 8 Hz, 1H), 7.26 (s, 1H), 6.73 (s, 1H), 6.49 (s,1H), 5.45 (s, 1H), 4.64-4.57  3 (m, 1H), 4.56-4.52 (m, 1H), 1.99 (d, J =12.0 Hz, 2H), 1.89 (s, 3H) 105

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-(((R)-1- hydroxy-butan-2- yl)amino) pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.38 (t, J = 7.2 Hz, 2H), 8.18 (s, 1H), 8.01 (d, J =5.6 Hz, 1H), 7.42 (s, 1H), 7.32- 7.26 (m, 3H), 6.84 (d, J = 5.6 Hz, 1H),6.74 (s, 1H), 6.36 (d, J = 7.6 Hz, 1H), 5.02-4.99 (m, 2H), 13 4.61 (d, J= 5.6 Hz, 1H), 3.81 (s, 1H), 3.71 (t, J = 5.6 Hz, 1H), 3.47-3.44 (m,1H), 3.34-3.27 (m, 1H), 1.67-1.65 (m, 1H), 1.63-1.61 (m, 1H), 1.07 (t, J= 7.2 Hz, 1H), 0.87 (t, J = 6.8 Hz, 3H) 106

1-(5-chloro- 2-(phenyl- amino) pyridin-4-yl)- N-(1-(3- chlorophenyl)-2-hydroxy- ethyl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆):δ 9.44 (s, 1H), 8.41 (s, 1H), 8.38 (d, J = 4.0 Hz, 1H), 8.16 (s, 1H),8.02 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.44 (s, 1H), 7.33- 7.30 (m,2H), 7.29- 7.27 (m, 3H), 6.93 (s, 2H), 5.02-5.01 (m, 2H), 3.72 (t, 10 J= 5.6 Hz, 2H) 107

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((4-fluoro-phenyl)amino)- 5-methyl- pyrimidin-4- yl)-4-methyl- 1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H), 8.43 (s, 1H),8.14 (d, J = 7.6 Hz, 1H), 8.10 (s, 1H), 7.75-7.72 (m, 2H), 7.43 (s, 1H),7.33 (d, J = 6.0 Hz, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 7.11 (t, J = 8.8Hz, 2H), 5.01- 4.93 (m, 1H), 4.92 (t, J = 5.2 Hz, 1H), 3.64 (s, 2H),2.33  3 (s, 3H), 2.19 (s, 3H) 108

1-(2-((4- fluoro-phenyl) amino)-5- methyl- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 4-methyl- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.66 (s, 1H), 8.43 (s, 1H), 8.14 (d, J = 8 Hz, 1H),8.12 (d, J = 8.4 Hz, 1H), 7.73-7.71 (m, 2H), 7.43 (s, 2H), 7.36-7.73 (m,2H), 7.30-7.27 (m, 1H), 7.25-7.21 (m, 1H), 7.11 (t, J = 8.8 Hz, 2H),5.03- 4.98 (m, 1H), 4.91 (t, J = 5.6 Hz, 1H),  3 3.66-3.63 (m, 2H), 2.33(s, 3H), 2.19 (s, 3H). 109

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- (((S)-1- hydroxy-butan-2-yl) amino) pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.18 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 6 Hz, 2H), 7.41(s, 1H), 7.36 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 2 Hz, 1H),6.74-6.72 (m, 2H), 6.65 (s, 1H), 6.32 (d, J = 7.6 Hz, 13 1H), 5.05-5.01(m, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.61 (s, 1H), 3.82 (d, J = 4.4 Hz,1H), 3.65-3.63 (m, 2H), 3.48-3.43 (m, 1H), 3.37-3.27 (m, 1H), 1.69-1.65(m, 1H), 1.47-1.41 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H). 110

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((4-fluoro- phenyl)-amino) pyrimidin-4- yl)-4-methyl- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.75 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.29 (s, 1H),8.22 (d, J = 8 Hz, 1H), 7.75 (t, J = 8.8 Hz, 2H), 7.46 (d, J = 14 Hz,2H), 7.33 (s, 2H), 7.29 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.06 (d, J =5.6 Hz, 1H), 5.00 (d, J =  3 6.4 Hz, 1H), 4.92 (t, J = 6 Hz, 1H), 3.64(s, 2H), 2.18 (s, 3H). 111

1-(2-((2- chloro-4- fluorophenyl) amino) pyrimidin-4- yl)-N-(1-(3-chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 8Hz, 1H), 8.19 (s, 1H), 7.68 (t, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.50 (d,J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.32- 7.24 (m, 4H), 7.14 (d, J = 5.2 Hz,1H), 6.78 (s, 1H), 5.01  3 (d, J = 7.2 Hz, 1H), 4.92 (s, 1H), 3.65 (s,2H). 112

(S)-1-(2-((2- chloro-4- fluorophenyl)- amino) pyrimidin-4- yl)-N-(1-(3-chlorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 8Hz, 1H), 8.19 (s, 1H), 7.68 (t, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.49 (d,J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.32- 7.24 (m, 4H), 7.14 (d, J = 5.2 Hz,1H), 6.78 (s, 1H), 5.01  3 (d, J = 7.2 Hz, 1H), 4.92 (s, 1H), 3.65 (s,2H). 113

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((4-fluoro- phenyl)amino)-5- methyl- pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.46 (s, 1H), 8.28 (d, J = 8 Hz, 1H),8.03 (s, 1H), 7.73-7.70 (m, 2H), 7.43 (s, 2H), 7.34 (d, J = 5.6 Hz, 2H),7.27 (s, 1H), 7.11 (t, J = 8.8 Hz, 2H), 6.78 (s, 1H), 5.07- 5.01 (m,1H), 4.93 (t, J = 5.6 Hz, 1H),  3 3.68-3.62 (m, 2H), 2.31 (s, 3H). 114

1-(2-((4- fluoro-phenyl) amino)-5- methyl- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 9.69 (s, 1H), 8.46 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.02(s, 1H), 7.73-7.70 (m, 2H), 7.44 (s, 1H), 7.37 (d, J = 7.6 Hz, 2H),7.35-7.28 (m, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H),6.79 (s, 1H), 5.05 (d,  3 J = 6.4 Hz, 1H), 4.87 (s, 1H), 3.65 (m, 2H),2.31 (s, 3H). 115

N-(1-(3-chloro- phenyl)-2- hydroxy- ethyl)-1-(2- (cyclopropyl- amino)-5-methyl- pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.28 (s, 1H), 8.24 (d, J = 11.2 Hz, 1H), 7.96 (s, 1H), 7.41(d, J = 6.4 Hz, 3H), 7.28- 7.26 (m, 3H), 6.74 (s, 1H), 5.05-5.00 (m,1H), 4.92 (s, 1H), 3.65 (t, J = 5.6 Hz, 2H), 2.23 (s,  3 3H), 0.66-0.63(m, 2H), 0.45 (s, 3H). 116

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (cyclopropyl- amino)pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ8.47 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.07 (d, J = 5.2Hz, 1H), 7.42 (s, 1H), 7.32 (t, J = 5.6 Hz, 3H), 7.03 (s, 1H), 6.96 (d,J = 4.0 Hz, 1H), 6.80 (s, 1H), 5.04-5.01 13 (m, 2H), 3.72 (t, J = 5.2Hz, 2H), 2.56-2.48 (m, 1H), 1.33-1.22 (m, 2H), 0.43 (s, 2H). 117

N-(2-hydroxy- 1-phenyl- ethyl)-1-(5- methyl-2-((1- phenylethyl) amino)pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ8.21 (s, 1H), 8.19-8.16 (m, 1H), 7.91 (br s, 1H), 7.72 (d, J = 6.4 Hz,1H), 7.47- 7.34 (m, 4H), 7.31- 7.01 (m, 7H), 6.72- 6.71 (m, 1H), 5.04(t, J = 6.0 Hz, 2H), 4.85 (t, J = 6.0 Hz,  3 1H), 3.67-3.62 (m, 2H),3.39-3.23 (m, 1H), 2.18 (s, 3H), 1.28-1.22 (m, 1H), 1.07 (t, J = 7.2 Hz,1H). 118

1-(2-((4- fluoro-phenyl) amino)-5- methyl- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 9.80 (s, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.29 (d, J = 8.4Hz, 1H), 8.15 (s, 1H), 7.69 (t, J = 5.2 Hz, 2H), 7.36 (d, J = 7.2 Hz,2H), 7.26 (t, J = 6.8 Hz, 2H), 7.21 (t, J = 6.8 Hz, 1H), 7.12 (t, J =9.6 Hz, 2H), 5.04-4.97 (m,  6 2H), 3.71 (d, J = 4.4 Hz, 2H), 2.26 (s,3H). 119

N-(1-amino- 3-phenyl- propan-2-yl)- 1-(2-((4- fluoro-phenyl) amino)pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.15 (d, J = 9.2 Hz, 1H), 8.16 (d, J = 6 Hz, 1H), 7.90 (s, 1H), 7.66 (t,J = 4.4 Hz, 3H), 7.38 (s, 1H), 7.23 (d, J = 4 Hz, 4H), 7.14-7.12 (m,2H), 7.01 (d, J = 4.4 Hz, 1H), 6.90 (t, J = 10 Hz, 1H), 6.71 (s, 1H),4.02 (d, J = 5.6 Hz, 1H),  9 2.88-2.85 (m, 1H), 2.77-2.72 (m, 1H),2.65-2.48 (m, 2H), 2.15 (s, 1H), 1.85 (s, 2H). 120

N-(2-hydroxy- 1-phenylethyl)- 1-(5-methyl-2- ((tetrahydro- 2H-pyran-4-yl)amino) pyrimidin-4- yl)-1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.25 (s, 1H), 8.19 (d, J = 8 Hz, 1H), 7.94 (s, 1H), 7.35 (d,J = 8 Hz, 3H), 7.29 (t, J = 6.8 Hz, 2H), 7.20 (t, J = 7.2 Hz, 2H), 6.74(s, 1H), 5.06- 5.00 (m, 1H), 4.85 (s, 1H), 3.86 (t, J =  3 14 Hz, 3H),3.64 (s, 2H), 3.37 (t, J = 10.4 Hz, 2H), 2.21 (s, 3H), 1.81 (d, J = 12Hz, 2H), 1.52-1.45 (m, 2H) 121

N-(2-hydroxy- 1-phenylethyl)- 1-(5-methyl- 2-((3,4,5- trimethoxy-phenyl)amino) pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.56 (s, 1H), 8.46 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H),8.09 (s, 1H), 7.47 (s, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.3 (t, J = 7.6Hz, 2H), 7.21 (t, J = 7.2 Hz, 3H), 6.7 (s, 1H), 5.04 (d, J = 7.2 Hz,1H), 4.85 (t, J = 5.6 Hz, 1H), 3.73 (s, 6H), 3.62  3 (s, 2H), 3.59 (s,3H), 2.32 (s, 3H) 122

1-(2-((2- chloro-4- fluorophenyl) amino)-5- (trifluoro- methyl)pyrimidin-4- yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.43 (s, 1H), 8.68 (s, 1H),8.32 (d, J = 8 Hz, 1H), 8.05 (s, 1H), 7.64-7.61 (m, 1H), 7.57-7.53 (m,1H), 7.35-7.26 (m, 5H), 7.22-7.18 (m, 2H), 6.68 (d, J = 1.6 Hz, 1H),5.00-4.95 (m, 1H), 4.83 (t, J = 5.6 Hz, 1H), 3.67- 3.56 (m, 2H)  3 123

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2- ((tetrahydro-furan-3- yl)amino) pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR (400 MHz,DMSO-d₆): δ 8.27 (t, J = 4.8 Hz, 2H), 7.96 (s, 1H), 7.48 (d, J = 6.0 Hz,1H), 7.40 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.28 (t, J =8.4 Hz, 1H), 6.75 (s, 1H), 5.05- 5.00 (m, 1H), 4.95  3 carboxamide (t, J= 5.6 Hz, 1H), 4.36 (br s, 1H), 3.89-3.78 (m, 2H), 3.72-3.63 (m, 3H),3.54-3.52 (m, 1H), 2.17 (s, 3H), 2.15- 2.08 (m, 1H), 1.90- 1.86 (m, 1H)124

1-(5-chloro- 2-(phenyl- amino) pyridin-4-yl)- N-(1-(3- chlorophenyl)-2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.35 (s, 1H), 8.34 (s, 1H), 8.21 (d, J = 8 Hz, 1H), 7.76 (s, 1H), 7.61(d, J = 7.6 Hz, 2H), 7.42 (s, 1H), 7.34-7.26 (m, 5H), 7.17 (t, J = 2.8Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.87 10 (s, 1H), 6.78 (s, 1H),5.06-5.0 (m, 1H), 4.92 (t, J = 6 Hz, 1H), 3.67-3.62 (m, 2H) 125

(S)-N-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1-(2-((4-fluoro- phenyl)- amino)-5- methyl- pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.7 (s, 1H), 8.46 (s, 1H), 8.27(d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.73-7.71 (m, 2H), 7.57 (d, J = 6 Hz,1H), 7.44 (t, J = 2 Hz, 1H), 7.36-7.34 (m, 2H), 7.14-7.09 (m, 2H), 6.77(s, 1H), 5.06-5.01 (m, 1H), 4.94 (t,  3 J = 5.6 Hz, 1H), 3.68-3.61 (m,2H), 2.31 (s, 3H) 126

(S)-N-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-((3,4,5- trimethoxy- phenyl)amino) pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.57 (s, 1H), 8.47 (s, 1H), 8.25(d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.57 (d, J = 6 Hz, 1H), 7.48 (s, 1H),7.36 (d, J = 6.8 Hz, 2H), 7.19 (s, 2H), 6.79 (s, 1H), 5.04 (d, J = 7.2Hz, 1H), 4.93 (s, 1H), 3.73 (s, 6H), 3.64 (s, 2H), 3.60 (s, 3H),  3 2.32(s, 3H) 127

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((1-methoxy- butan-2-yl)amino)- 5-methyl- pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR (400 MHz,DMSO-d₆): δ 8.24 (s, 2H), 7.95 (br s, 1H), 7.42 (s, 1H), 7.37 (s, 1H),7.34 (s, 2H), 7.28 (s, 1H), 6.97 (br s, 1H), 6.74 (s, 1H), 5.03 (d, J =7.2 Hz, 1H), 4.92 (s, 1H), 4.0 (s, 1H), 3.65 (d, J = 4.8 Hz,  3carboxamide 2H), 3.35 (d, J = 6 Hz, 2H), 3.22 (s, 3H), 2.31 (s, 3H),1.59 (s, 1H), 1.45- 1.43 (m, 1H), 0.86 (t, J = 7.6 Hz, 3H) 128

N-(2- hydroxy-1- phenylethyl)- 1-(5- methyl-2- ((tetrahydro- furan-3-yl)amino) pyrimidin-4- yl)-1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.28 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.45(s, 1H), 7.37 (t, J = 8.4 Hz, 3H), 7.30 (t, J = 7.2 Hz, 2H), 7.21 (t, J= 6.8 Hz, 1H), 6.75 (s, 1H), 5.06- 5.01 (m, 1H), 4.86  3 (s, 1H), 4.36(br s, 1H), 3.89-3.78 (m, 2H), 3.72-3.63 (m, 3H), 3.54-3.52 (m, 1H),2.17 (s, 3H), 2.15-2.08 (m, 1H), 1.90-1.86 (m, 1H) 129

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methoxy- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.43 (s, 1H), 8.27 (d, J = 8 Hz, 1H),8.21 (s, 1H), 7.76-7.72 (m, 1H), 7.63 (t, J = 2.8 Hz, 1H), 7.49-7.46 (m,1H), 7.35 (d, J = 7.6 Hz, 2H), 7.27 (t, J = 8.4 Hz, 2H), 7.24-7.19 (m,2H), 6.79-6.78 (m, 1H),  3 5.05-5.0 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H),3.92 (s, 3H), 3.68-3.62 (m, 2H) 130

1-(2-(ethyl- amino)-5- methyl- pyrimidin-4- yl)-N-(2- hydroxy-1-phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.25(s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.35 (d, J = 7.6 Hz,3H), 7.29 (t, J = 7.6 Hz, 2H), 7.22-7.16 (m, 2H), 6.74 (s, 1H), 5.06-5.01 (m, 1H), 4.86 (t, J = 6 Hz, 1H),  3 3.67-3.62 (m, 2H), 3.30-3.23(m, 2H), 2.21 (s, 3H), 1.11 (t, J = 6.8 Hz, 3H) 131

1-(2-((2,3- dihydro- benzo[b][1,4] dioxin-6-yl)- amino)-5- methyl-pyrimidin-4- yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.42 (s, 1H),8.22 (d, J = 8 Hz, 1H), 8.0 (s, 1H), 7.41 (t, J = 2.8 Hz, 1H), 7.41-7.34(m, 5H), 7.22 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 2.8 Hz, 1H), 6.79 (s,1H), 6.75 (d, J = 8.8 Hz, 1H), 5.06 (t, J = 7.2 Hz, 1H), 4.86 (t, J =5.2  3 Hz, 1H), 4.20-4.16 (m, 4H), 3.66-3.64 (m, 2H), 2.29 (s, 3H) 132

1-(2-(benzo- furan-5- ylamino)-5- methyl- pyrimidin-4- yl)-N-(1-(3-chlorophenyl)- 2-hydroxy- ethyl)-1H- imidazole-4- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.77 (s, 1H), 8.54 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H),8.36 (d, J = 0.8 Hz, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.91 (d, J = 2 Hz,1H), 7.54-7.48 (m, 2H), 7.44 (s, 1H), 7.34 (d, J = 5.2 Hz, 2H), 7.29 (t,J = 1.6 Hz, 1H), 6.90 (d,  6 J = 1.6 Hz, 1H), 5.02 (d, J = 8 Hz, 2H),3.72 (d, J = 5.6 Hz, 2H), 2.27 (s, 3H) 133

N-((S)-1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1- (2-(((S)-1-hydroxy- butan-2-yl) amino)-5- methyl- pyrimidin-4- yl)-1H-pyrrole-1HNMR (400 MHz, DMSO-d₆): 8.24 (d, J = 5.2 Hz, 2H), 7.94 (s, 1H), 7.56(d, J = 7.2 Hz, 1H), 7.36-7.32 (m, 3H), 6.79 (d, J = 8 Hz, 1H), 6.73 (s,1H), 5.03-4.99 (m, 1H), 4.93 (t, J = 6 Hz, 1H), 4.56 (t, J = 5.6 Hz,1H), 3.81  3 3-carboxamide (br s, 1H), 3.67- 3.62 (m, 2H), 3.47- 3.43(m, 1H), 3.35- 3.33 (m, 1H), 2.14 (s, 3H), 1.68-1.62 (m, 1H), 1.22 (s,1H), 0.86 (t, J = 7.6 Hz, 3H) 134

N-(1-amino-3- phenylpropan- 2-yl)-1-(2- ((2,2-difluoro- benzo[d][1,3]dioxol-5-yl) amino)-5- methyl- pyridin-4-yl)- 1H-1,2,3- triazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 11.29 (s, 1H), 9.49 (s, 1H),9.04 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 7.93 (d, J = 1.6Hz, 1H), 7.33-7.14 (m, 8H), 6.94 (d, J = 9.6 Hz, 1H), 4.29 (s, 1H), 3.50(s, 1H), 3.16- 2.83 (m, 3H), 1.97 (s, 3H) 12 135

N-(2- acetamido-1- phenylethyl)- 1-(2-((4- fluorophenyl)- amino)-5-methyl- pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 9.12 (s, 1H), 8.33 (s, 1H), 8.11 (d, J = 18.4 Hz, 2H), 7.63(s, 3H), 7.35 (s, 5H), 7.11 (s, 3H), 6.71 (d, J = 10 Hz, 2H), 5.08 (s,1H), 3.46 (s, 2H), 2.15 (s, 3H), 1.78 (s, 3H)  9 136

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(2-((2,2- difluoro-benzo[d][1,3] dioxol-5- yl)amino)-5- methyl- pyrimidin-4- yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.95 (s,1H), 7.69 (d, J = 1.6 Hz, 1H), 7.34 (t, J = 2.8 Hz, 1H), 7.23 (s, mergedwith CDCl3 peak, 1H), 7.06-6.99 (m, 2H), 6.78-6.77 (m, 1H), 3.86 (s,3H), 2.40 (s, 3H).  4 137

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (2-((2,3- dihydro-benzofuran-5- yl)-mino)-5- methyl- pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.41 (s, 1H), 8.4 (s, 1H), 8.27(d, J = 8 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.43 (s, 2H),7.34-7.27 (m, 4H), 6.76 (s, 1H), 6.67 (d, J = 8.8 Hz, 1H), 5.06-5.01 (m,1H), 4.92 (d, J = 6 Hz, 1H), 4.47 (t, J = 8.8  3 Hz, 2H), 3.66 (t, J =5.6 Hz, 2H), 3.15 (t, J = 8.8 Hz, 2H), 2.29 (s, 3H) 138

1-(2-((2,3- dihydro- benzofuran-5- yl)amino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.4 (s, 1H), 8.39 (s, 1H), 8.23 (d, J = 8 Hz, 1H), 8.03(s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 7.37-7.34 (m, 3H), 7.32-7.28 (m,2H), 7.21 (t, J = 7.2 Hz, 1H), 6.77 (s, 1H), 6.67 (d, J = 8.4 Hz, 1H),5.07-5.02 (m, 1H),  3 4.86 (s, 1H), 4.47 (t, J = 8.4 Hz, 2H), 3.65 (t, J= 9.2 Hz, 2H), 3.15 (t, J = 8.8 Hz, 2H), 2.29 (s, 3H) 139

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (2-((2,3- dihydro-benzo[b][1,4] dioxin-6-yl) amino)-5- methyl- pyrimidin-4- yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.47 (s, 1H), 8.42(s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.43 (s, 2H), 7.33 (s,3H), 7.29 (s, 1H), 7.12-7.09 (m, 1H), 6.76 (t, J = 7.2 Hz, 2H), 5.03 (t,J = 7.6 Hz, 1H), 4.93 (s, 1H), 4.18 (t, J = 5.6 Hz, 4H), 3.66 (d, J =4.4 Hz, 2H),  3 2.29 (s, 3H) 140

1-(2-((1H- indazol-5-yl) amino)-5- methyl- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 12.87 (s, 1H), 9.61 (s, 1H), 8.45 (s, 1H), 8.26 (d, J = 8Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.55 (d, J = 8 Hz,1H), 7.45 (t, J = 4.4 Hz, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.30 (t, J =7.2 Hz, 2H), 7.21 (d, J =  3 6.8 Hz, 1H), 6.78 (s, 1H), 5.08-505 (m,1H), 4.87 (t, J = 5.6 Hz, 1H), 3.66 (s, 2H), 2.31 (s, 3H) 141

N-(2-hydroxy- 1-phenylethyl)- 1-(5- methyl-2- ((tetrahydro- 2H-pyran-3-yl)amino)- pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.26 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.36(d, J = 12 Hz, 3H), 7.29 (t, J = 12 Hz, 3H), 7.20 (t, J = 6.8 Hz, 1H),7.10 (s, 1H), 6.75 (s, 1H), 5.04 (d, J = 7.2 Hz, 1H),  3 4.86 (s, 1H),3.84 (d, J = 8.4 Hz, 2H), 3.72 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 4.0Hz, 2H,), 3.08 (t, J = 10.8 Hz, 1H), 2.22 (s, 3H), 1.94 (br s, 1H), 1.66(s, 1H), 1.54 (d, J = 8.0 Hz, 2H) 142

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((4-fluoro-2- methoxy-phenyl)amino)- 5-methyl- pyrimidin-4- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.40 (s, 1H), 8.27 (t, J = 8.8 Hz, 2H), 8.0(s, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.41 (s, 2H), 7.34-7.27 (m, 3H),6.98-6.95 (m, 1H), 6.76 (s, 2H), 5.06-5.01 (m, 1H), 4.93 (t, J = 5.2 Hz,1H), 3.82 (s, 3H), 3.68-3.64 (m, 2H),  3 2.30 (s, 3H) 143

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((3-fluoro-2- methoxy-phenyl)amino)- 5-methyl- pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR (400 MHz,DMSO-d₆): δ 9.66 (s, 1H), 8.46 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.02(s, 1H), 7.70-7.67 (m, 1H), 7.43-7.40 (m, 3H), 7.33-7.27 (m, 3H), 7.09(t, J = 9.6 Hz, 1H), 6.79 (s, 1H), 5.27 (d, J = 7.6 Hz,  3 carboxamide1H), 4.95-4.85 (m, 1H), 3.78 (s, 3H), 3.66 (d, J = 4.8 Hz, 2H), 2.31 (s,3H) 145

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- (pyrrolidin-3- ylamino)pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ8.20 (s, 1H), 8.01 (t, J = 5.6 Hz, 2H), 7.40 (d, J = 10.4 Hz, 2H), 7.30(d, J = 15.2 Hz, 3H), 6.78- 6.72 (m, 3H), 6.59 (s, 1H), 5.02 (d, J = 7.2Hz, 1H), 4.94 (s, 1H), 4.26 13 (s, 1H), 3.65 (s, 2H), 3.09 (d, J = 11.2Hz, 2H), 2.95 (s, 2H), 2.85 (s, 1H), 2.04 (t, J = 6.8 Hz, 1H), 1.62 (s,1H) 146

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- (((S)-1- hydroxy-butan-2-yl) amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 8.24 (d, J = 7.2 Hz, 2H), 7.94 (s, 1H), 7.42- 7.26 (m, 5H),6.80- 6.74 (m, 2H), 5.05- 5.00 (m, 1H), 4.94- 4.91 (m, 1H), 4.57- 4.55(m, 1H), 3.83 (br s, 1H), 3.65 (d, J = 4.8 Hz, 2H),  3 pyrrole-3-3.47-3.42 (m, 1H), carboxamide 3.37-3.32 (m, 1H), 2.21 (s, 3H), 1.68-1.61 (m, 1H), 1.45- 1.38 (m, 1H), 0.862 (t, J = 7.2 Hz, 3H) 147

1-(2-((1,3- dihydroxy- propan-2-yl) amino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.25 (s, 1H), 8.20 (d, J = 8 Hz, 1H), 7.95 (s, 1H),7.39-7.28 (m, 7H), 7.22-7.18 (m, 1H), 6.75 (s, 1H), 6.59 (d, J = 8 Hz,1H), 5.06-5.01 (m, 1H), 4.86 (t, J = 6 Hz, 1H), 4.57 (t,  3 J = 5.2 Hz,2H), 3.93-3.89 (m, 1H), 3.66 (t, J = 5.6 Hz, 2H), 3.51-3.48 (m, 2H),2.22 (s, 3H) 148

N-(2- hydroxy-1- phenylethyl)- 1-(2-((4- methoxy-3- (2-(4-methyl-piperazin-1- yl)ethoxy)- phenyl)amino)- 5-methyl- 1HNMR (400 MHz,DMSO-d₆): δ 9.46 (s, 1H), 8.43 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.03(s, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.44 (d, J = 2.4 Hz,2H), 7.36 (d, J = 7.6 Hz, 2H), 7.30 (t,  3 pyrimidin-4- J = 6.8 Hz, 2H),yl)-1H- 7.21 (t, J = 7.2 Hz, pyrrole-3- 1H), 7.16-7.14 (m, carboxamide1H), 6.87 (d, J = 5.2 Hz, 1H), 6.80 (s, 1H), 5.07-5.02 (m, 1H), 4.88 (s,1H), 4.02 (s, 2H), 3.70 (s, 3H), 3.65 (s, 2H), 2.65 (s, 3H), 2.30 (s,4H), 2.25 (s, 3H) 149

N-(2- hydroxy-1- phenylethyl)- 1-(5-methyl- 2-(pyridin-2- ylamino)pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.76 (s, 1H), 8.22 (s, 1H), 8.20 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 8 Hz,1H), 7.86 (s, 1H), 7.66-7.62 (m, 2H), 7.54 (d, J = 8 Hz, 1H), 7.37-7.36(m, 2H), 7.31 (t, J = 7.2 Hz, 2H),  3 7.21 (t, J = 7.6 Hz, 1H), 7.09 (s,1H), 6.84 (t, J = 6.4 Hz, 1H), 6.77 (s, 1H), 5.07-5.02 (m, 1H), 4.86 (t,J = 5.6 Hz, 1H), 3.67-3.62 (m, 2H), 2.17 (s, 3H) 150

2-(1-(2-((2- chloro-4- fluorophenyl)- amino)-5- methyl- pyrimidin-4-yl)-1H- pyrrole-3- carboxamido)- 2-phenylethyl 2-amino-4- methyl-pentanoate 1HNMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.49-8.43 (m, 1H),8.39 (s, 1H), 7.93 (s, 1H), 7.69-7.66 (m, 1H), 7.49-7.38 (m, 6H),7.36-7.30 (m, 1H), 7.28-7.19 (m, 1H), 6.74 (s, 1H), 5.37- 5.35 (m, 1H),4.50- 4.45 (m, 1H), 4.31- 4.28 (m, 1H), 3.67 (s, 1H), 2.99 (s, 1H), 2.28(s, 3H), 1.71 (s, 1H), 1.61-1.55  3, 18 (m, 1H), 1.43-1.35 (m, 2H), 0.70(t, J = 3.2 Hz, 6H) 151

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-((tetrahydro- furan-3- yl)amino) pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR(400 MHz, DMSO-d₆): δ 8.28 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.95 (s,1H), 7.45-7.39 (m, 3H), 7.36-7.26 (m, 3H), 6.75 (s, 1H), 5.05-5.00 (m,1H), 4.94-4.91 (t, J = 5.6 Hz, 1H), 4.35 (br s, 1H),  3 carboxamide3.89-3.78 (m, 2H), 3.72-3.65 (m, 3H), 3.54-3.51 (m, 1H), 2.17 (s, 3H),2.15- 2.09 (m, 1H), 1.89- 1.86 (m, 1H) 152

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-((tetrahydro- 2H-pyran-3- yl)amino) pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.25 (d, J = 13.6 Hz, 2H), 7.95(s, 1H), 7.42 (s, 1H), 7.37- 7.28 (m, 4H), 7.11 (s, 1H), 6.74 (s, 1H),5.03 (d, J = 6.4 Hz, 1H), 4.93 (s, 1H), 3.83 (s, 2H), 3.74- 3.65 (m,3H), 3.09 (d, J = 10 Hz, 1H), 2.22 (s, 4H), 1.94 (s, 1H), 1.66 (s, 1H),1.55 (s, 2H)  3 153

1-(2-((4- fluoro-phenyl) amino)-5- methyl- pyrimidin-4- yl)-N-(2-hydroxy-1- phenylethyl)- 2-methyl-1H- imidazole-4- carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 9.89 (s, 1H), 8.60 (s, 1H), 8.21 (d, J = 8.4 Hz,1H), 7.92 (s, 1H), 7.70-7.67 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.31 (t,J = 7.2 Hz, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 8.8 Hz, 2H),5.02 (d, J = 4.8 Hz, 2H), 3.77-3.69 (m,  5 2H), 2.35 (s, 3H), 2.03 (s,3H) 154

1-(2-((4- fluoro-3- methoxy- phenyl) amino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.75 (s, 1H), 8.49 (s, 1H), 8.28 (d, J = 8 Hz, 1H),8.09 (s, 1H), 7.82-7.80 (m, 1H), 7.48 (s, 1H), 7.38- 7.08 (m, 7H), 6.82(s, 1H), 5.09-5.03 (m, 1H), 4.92-4.89 (m, 1H), 3.81 (s, 3H), 3.66 (s,2H), 2.34 (s, 3H)  3 155

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((4-fluoro- phenyl)amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole- 4-carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 8.54 (s, 1H), 8.42 (d, J = 8 Hz,1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.69 (m, 2H), 7.44 (s, 1H), 7.33 (s,2H), 7.29 (s, 1H), 7.12 (t, J = 8.4 Hz, 2H), 5.04 (s, 2H), 3.73 (s, 2H),2.27 (s, 3H)  6 156

N-((S)-1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-3- yl)amino)- pyrimidin-4- yl)-1H- pyrrole-3-1HNMR (400 MHz, DMSO-d₆): δ 8.25 (t, J = 4.8 Hz, 2H), 7.95 (s, 1H), 7.42(s, 1H), 7.37 (s, 1H), 7.33 (d, J = 6.4 Hz, 1H), 7.27 (d, J = 3.4 Hz,2H), 7.10 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 5.05- 5.00 (m, 1H), 4.93  3carboxamide (t, J = 5.6 Hz, 1H), 3.84 (d, J = 8.0 Hz, 2H), 3.72 (d, J =10.8 Hz, 1H), 3.67- 3.63 (m, 1H), 3.08 (t, J = 10.4 Hz, 1H), 2.22 (s,3H), 1.94 (s, 1H), 1.66 (s, 1H), 1.53 (d, J = 8.8 Hz, 2H) 157

N-((S)-1- (3-chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-((tetrahydro- furan-3- yl)amino) pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR(400 MHz, DMSO-d₆): δ 8.28- 8.23 (m, 2H), 7.95 (s, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.45 (d, J = 5.6 Hz, 1H), 7.39-7.32 (m, 3H), 5.05-4.99 (m, 1H),4.94 (s, 1H), 4.36 (br s, 1H), 3.89- 3.80 (m, 2H), 3.70- 3.64 (m, 3H),3.53  3 carboxamide (s, 1H), 2.23 (s, 3H), 2.15-2.10 (m, 1H), 1.82 (d, J= 6.0 Hz, 1H) 158

N-(2- acetamido-1- (3-chloro- phenyl)- ethyl)-1-(2- ((2,2-difluoro-benzo[d][1,3] dioxol-5-yl)- amino)-5- methyl- pyrimidin-4- yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.90 (s, 1H), 8.5 (s,1H), 8.44 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H),7.46 (s, 1H), 7.41 (d, J = 11.2 Hz, 2H), 7.35-7.30 (m, 4H), 6.75 (s,1H), 5.0 (br s, 1H), 3.47 (br s, 2H), 2.32 (s, 3H), 1.77 (s, 3H)  4, 19159

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(2-((4- fluoro-phenyl)amino)-5- methyl- pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.07 (s, 1H), 8.15-8.12 (m, 2H), 7.67-7.61 (m, 3H),7.39 (s, 1H), 7.36-7.26 (m, 3H), 7.09-7.06 (m, 3H), 6.75 (s, 1H), 6.69(s, 1H), 4.90 (d, J = 6.8 Hz, 1H), 2.84 (d, J = 7.2 Hz, 2H), 1.88 (br s,2H), 2.14 (s, 3H)  9 160

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((2,2-difluoro-benzo[d][1,3] dioxol-4-yl) amino)-5- methyl- pyrimidin-4- 1HNMR (400MHz, DMSO-d₆): δ 9.71 (s, 1H), 8.46 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.98 (s, 1H), 7.41 (s, 2H), 7.34- 7.29 (m, 4H), 7.16 (t, J = 8 Hz, 2H),6.77 (s, 1H), 5.02 (d, J = 6.8 Hz, 1H),  3 yl)-1H- 4.93 (s, 1H), 3.65pyrrole-3- (s, 2H), 2.33 (s, 3H) carboxamide 161

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-(((S)-tetra- hydrofuran- 3-yl)amino) pyrimidin-4- yl)-1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.28 (s, 1H), 8.24 (d, J = 8.4Hz, 1H), 7.96 (s, 1H), 7.46-7.39 (m, 3H), 7.36-7.28 (m, 3H), 6.75 (s,1H), 5.02 (t, J = 6.8 Hz, 1H), 4.93 (s, 1H), 4.37 (br s, 1H), 3.89-3.79(m,  3 2H), 3.72-3.66 (m, 3H), 3.54-3.51 (m, 1H), 2.18 (s, 3H),2.16-2.09 (m, 1H), 1.89-1.86 (m, 1H) 162

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-(((R)-tetra- hydrofuran-3- yl)amino) pyrimidin-4- yl)-1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.28 (s, 1H), 8.24 (d, J = 8.0Hz, 1H), 7.96 (s, 1H), 7.46-7.39 (m, 3H), 7.34-7.28 (m, 3H), 6.75 (s,1H), 5.03 (d, J = 6.8 Hz, 1H), 4.93 (s, 1H), 4.37 (br s, 1H), 3.89-3.79(m,  3 2H), 3.72-3.66 (m, 3H), 3.53 (t, J = 4.0 Hz, 1H), 2.15 (s, 3H),2.16-2.09 (m, 1H), 1.87 (t, J = 6.4 Hz, 1H) 163

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((2,3-dihydro-benzofuran-5- yl)amino) pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 8.88 (s, 1H), 8.42-8.37 (m, 2H), 8.20-8.16 (m,2H), 7.51 (s, 1H), 7.42 (s, 1H), 7.32-7.28 (m, 4H), 7.21 (d, J = 8.4 Hz,1H), 7.05 (d, J = 4.8 Hz, 1H), 6.88 (s, 1H), 6.8 (d, J = 8.4 Hz, 1H),5.02 (br s, 2H), 4.47 (t, 13 J = 8.8 Hz, 2H), 3.72 (s, 2H), 3.15 (t, J =8.4 Hz, 2H) 164

N-(2-amino- 1-(3-chloro- 4-fluoro- phenyl)ethyl)- 1-(2-((4-fluorophenyl)- amino)-5- methyl- pyridin-4-yl)- 1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.08 (s, 1H), 8.15-8.12 (m,2H), 7.66-7.14 (m, 3H), 7.54 (d, J = 6.8 Hz, 1H), 7.34 (d, J = 7.2 Hz,2H), 7.09-7.06 (m, 3H), 6.74 (s, 1H), 6.68 (s, 1H), 4.89 (d, J = 7.2 Hz,1H), 2.82 (s, 2H), 2.14 (s, 3H) 11 165

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (5-methyl- 2-((tetra-hydrofuran-3- yl)amino) pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 8.11 (d, J = 8 Hz, 1H), 7.96 (s, 1H), 7.58 (s,1H), 7.42 (s, 1H), 7.35-7.26 (m, 3H), 7.02 (s, 1H), 6.76 (d, J = 6 Hz,1H), 6.71 (s, 1H), 6.38 (s, 1H), 5.05-4.99 (m, 1H), 4.91 (t, 11 J = 5.6Hz, 1H), 4.35 (d, J = 5.2 Hz, 1H), 3.86-3.77 (m, 2H), 3.72-3.62 (m, 3H),3.50-3.28 (m, 1H), 2.19-2.14 (m, 1H), 2.05 (s, 3H), 1.79-1.71 (m, 1H)166

1-(2-((2- chloro-4- fluorophenyl) amino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.47 (s, 1H), 8.39(d, J = 8 Hz, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.65 (t, J = 6.4 Hz, 1H),7.48 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.28 (s, 3H), 7.22 (t, J = 8.4Hz, 1H), 5.02 (d, J = 5.2 Hz, 2H), 3.71 (d, J =  6 5.2 Hz, 2H), 2.25 (s,3H) 167

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- (((R)-1- hydroxy-butan-2- yl)amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 8.24 (d, J = 6.4 Hz, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.38(s, 1H), 7.32-7.26 (m, 3H), 6.79 (d, J = 8 Hz, 1H), 7.74 (s, 1H),5.05-5.0 (m, 1H), 4.92 (t, J = 6 Hz, 1H), 4.56 (t, J =  3 pyrrole-3- 5.6Hz, 1H), 3.82 carboxamide (d, J = 5.2 Hz, 2H), 3.66-6.63 (m, 1H),3.46-3.42 (m, 1H), 3.37-3.28 (m, 1H), 2.21 (s, 3H), 1.68- 1.61 (m, 1H),1.45- 1.38 (m, 1H), 0.86 (t, J = 7.6 Hz, 1H) 168

1-(5-chloro- 2-(((R)-1- hydroxy- butan-2-yl) amino) pyridin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- imidazole-4- 1HNMR (400MHz, DMSO-d₆): δ 8.37 (d, J = 8 Hz, 1H), 8.14 (t, J = 10.4 Hz, 1H), 8.07(d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.50 (s, 1H), 7.36-7.28 (m, 4H), 6.82(d, J = 8 Hz, 1H), 6.65 (s, 1H), 5.01 (t, J = 5.6 Hz, 10 carboxamide2H), 4.62 (t, J = 5.2 Hz, 1H), 3.76 (s, 1H), 3.71 (t, J = 5.2 Hz, 2H),3.47-3.44 (m, 1H), 1.68-1.62 (m, 1H), 1.44-1.37 (m, 1H), 1.22 (s, 2H),0.88-0.85 (m, 3H) 169

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(2-((2- chloro-4-fluorophenyl) amino)-5- methyl- pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.4 (s, 2H), 7.93(s, 1H), 7.66 (t, J = 6.4 Hz, 1H), 7.45-7.36 (m, 6H), 7.23-7.20 (m, 1H),6.75 (s, 1H), 5.22 (s, 1H), 3.18 (s, 2H), 2.96 (s, 2H), 2.28 (s, 3H)  4170

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- ((tetrahydro-furan-3- yl)amino) pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.41 (s, 1H), 8.37 (d, J = 8 Hz, 1H), 8.21 (s, 1H),8.06 (d, J = 4 Hz, 1H), 7.42 (s, 1H), 7.32-7.26 (m, 3H), 6.95-6.91 (m,2H), 6.71 (s, 1H), 5.04-4.98 (m, 2H), 4.39 (s, 1H), 3.89- 13 3.81 (m,2H), 3.71 (t, J = 8 Hz, 3H), 3.55-3.50 (m, 1H), 2.21-2.14 (m, 1H),1.81-1.79 (m, 1H) 171

N-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-(pyridin-3- ylamino) pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.27 (s, 1H), 8.75 (s, 1H), 8.16 (d, J = 10.4 Hz, 3H),8.09 (d, J = 4 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.34 (t,J = 8.8 Hz, 2H), 7.29- 7.26 (m, 1H), 7.11 (s, 1H), 6.76 (s, 2H), 5.02(t, J = 6.8 Hz, 11, 3 1H), 4.93 (t, J = 6 Hz, 1H), 3.66-3.62 (m, 2H),2.16 (s, 3H) 172

1-(2- (benzo[d][1,3] dioxol-5- ylamino)-5- methyl- pyrimidin-4-yl)-N-(1-(4- fluorophenyl)- 2-hydroxy- ethyl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 9.54 (s, 1H), 8.43 (s, 1H), 8.23 (d, J = 8.4Hz, 1H), 7.99 (s, 1H), 7.41 (s, 4H), 7.12 (t, J = 9.2 Hz, 3H), 6.82 (d,J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.94 (s, 2H), 5.04 (d, J =7.2 Hz, 1H), 4.88 (t, J = 5.6 Hz,  3 1H), 3.65 (d, J = 6.4 Hz, 2H), 2.29(s, 3H) 173

1-(2-(chroman- 6-ylamino)- 5-methyl- pyrimidin-4- yl)-N-(2- hydroxy-1-phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.37(s, 1H), 8.39 (s, 1H), 8.23 (d, J = 8 Hz, 1H), 8.04 (s, 1H), 7.43 (d, J= 12 Hz, 2H), 7.36 (d, J = 8 Hz, 2H), 7.30 (d, J = 8 Hz, 3H), 7.20 (d, J= 8 Hz, 1H), 6.77 (s, 1H), 6.64 (d, J = 8 Hz, 1H), 5.04 (d, J = 8 Hz,1H), 4.85 (s, 1H),  3 4.07-4.0 (m, 2H), 3.65 (s, 2H), 2.72 (s, 2H), 2.29(s, 3H), 1.88 (s, 2H) 174

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-(pyrrolidin-3- ylamino) pyrimidin-4- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.27 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.95(s, 1H), 7.41 (d, J = 11.2 Hz, 2H), 7.30 (d, J = 12 Hz, 4H), 6.75 (s,1H), 5.02 (d, J = 6.8 Hz, 1H), 4.93 (s, 1H), 4.25 (s, 1H), 3.65 (s,  33H), 3.03-2.94 (m, 2H), 2.81-2.65 (m, 2H), 2.22 (s, 3H), 2.01-1.99 (m,1H), 1.77-1.61 (m, 1H) 175

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((4-fluoro-3-morpholino- phenyl)amino)- 5-methyl- pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.63 (s, 1H), 8.46 (s, 1H), 8.27(d, J = 8.0 Hz, 1H), 8.0 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.45 (d, J =12 Hz, 2H), 7.32 (s, 2H), 7.28-7.22 (m, 2H), 7.03 (t, J = 12.4 Hz, 1H),6.80 (s, 1H), 5.04 (d, J =  3 7.2 Hz, 1H), 4.93 (t, J = 5.2 Hz, 1H),3.67 (t, J = 13.6 Hz, 6H), 2.97 (s, 4H), 2.31 (s, 3H) 176

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (2-((2,2- difluoro-benzo[d][1,3] dioxol-5-yl) amino)- pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.95 (s, 1H), 8.44 (d, J = 5.6Hz, 1H), 8.32 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H), 7.9 (s, 1H), 7.7 (s,1H), 7.42 (br s, 2H), 7.34-7.28 (m, 4H), 7.2 (d, J = 5.6 Hz, 1H), 6.82(s, 1H), 5.04-5.02 (m, 1H), 3.70-3.60 (m, 3H)  3 177

N-(2-amino- 1-(3- chlorophenyl) ethyl)-1-(2- ((4-fluoro- phenyl)amino)-5-methyl- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 9.8 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 8.34(s, 1H), 8.15 (s, 1H), 7.84 (br s, 2H), 7.68 (s, 2H), 7.52 (s, 1H), 7.39(s, 3H), 7.71- 7.68 (m, 2H), 7.11 (t, J = 8.8 Hz, 2H), 4.93-4.92 (m,1H), 2.91-2.87 (m, 1H),  4 2.26 (s, 3H) 178

N-(2-hydroxy- 1-phenylethyl)- 1-(5-methyl- 2-((4-(4- (piperazin-1-yl)-piperidin- 1-yl)-phenyl) amino) pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.38 (s, 1H), 8.23(d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.41 (s,1H), 7.36 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.21 (d, J =6.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.78 (s, 1H), 5.04 (d, J = 7.2Hz, 1H) 4.86 (s, 1H), 3.62 (t, J = 11.6 Hz, 4H), 2.92 (s, 4H), 2.58 (s,6H), 2.28 (s, 3H), 1.79 (d, J = 10.8 Hz 3H), 1.49 (d, J = 10 Hz, 3H)  3179

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((4-fluoro- 3-(4-methyl-piperazine-1- carbonyl) phenyl)amino)- 5-methyl- 1HNMR (400 MHz,DMSO-d₆): δ 9.83 (s, 1H), 8.48 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 8.01 (s,1H), 7.74 (d, J = 6 Hz, 2H), 7.44 (d, J = 4.8 Hz, 2H), 7.32- 7.28 (m,3H), 7.19 (t, J = 9.2 Hz, 1H),  3 pyrimidin-4- 6.78 (s, 1H), 5.06-yl)-1H- 5.01 (m, 1H), 4.93 pyrrole-3- (t, J = 5.2 Hz, 1H), carboxamide3.65 (t, J = 5.2 Hz, 2H), 3.60 (br s, 2H), 3.23 (s, 2H), 2.32 (s, 5H),2.21 (s, 2H), 2.15 (s, 3H) 180

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-(phenyl-amino) pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.11 (s, 1H) 8.37 (d, J = 8 Hz, 1H), 8.17 (s, 1H), 8.09(s, 1H), 7.99 (s, 1H), 7.61 (d, J = 8 Hz, 2H) 7.44 (s, 1H), 7.33 (s,2H), 7.25 (t, J = 7.2 Hz, 3H), 6.88 (t, J = 6.8 Hz, 11 1H), 6.77 (s,1H), 5.02 (t, J = 5.2 Hz, 2H), 3.72-3.71 (m, 2H), 2.07 (s, 3H) 181

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- ((5-fluoro-2- methoxy-4-(morpholine- 4-carbonyl) phenyl)amino)- 5-methyl- pyrimidin-4- yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.55 (s, 1H), 8.30(d, J = 10.4 Hz, 2H), 8.23 (d, J = 12 Hz, 1H), 8.08 (s, 1H), 7.49 (s,1H), 7.42 (s, 1H), 7.32 (s, 2H), 7.28 (s, 1H), 7.02 (d, J = 6 Hz, 1H),6.79 (s, 1H), 5.04 (d, J = 7.2 Hz, 1H), 4.93 (t, J = 5.2 Hz, 1H), 3.88(s, 3H), 3.71- 3.62 (m, 7H), 3.53  3 (br s, 3H), 2.30 (s, 3H) 182

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2- ((3-methyl-4-(piperidin-4-yl) phenyl)amino) pyrimidin-4- yl)-1H-pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.50 (s, 1H), 8.43 (s, 1H),8.29 (d, J = 8 Hz, 1H), 8.06 (s, 1H), 7.51 (s, 1H), 7.5 (s, 1H), 7.47(s, 1H), 7.43 (d, J = 5.6 Hz, 1H), 7.33 (d, J = 6 Hz, 2H), 7.28 (d, J =6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 5.06- 5.01 (m, 1H),4.93 (br s, 1H), 3.65 (br s, 2H), 3.36 (d, J = 7.2 Hz, 1H),  3 3.08 (d,J = 12 Hz, 2H), 2.75-2.66 (m, 3H), 2.30 (s, 3H), 2.26 (s, 3H), 1.66-1.52 (m, 4H) 183

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-4- methyl-1-(2-(phenylamino) pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 9.14 (s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 10 Hz,2H), 7.65 (d, J = 8.0 Hz, 2H), 7.42 (s, 1H), 7.33 (s, 2H), 7.26 (t, J =8.0 Hz, 3H), 7.20 (s, 1H), 6.97 (t, J = 5.2 Hz, 1H),  7 6.88 (s, 2H),4.99 (d, J = 7.2 Hz, 1H), 4.93 (t, J = 5.2 Hz, 1H), 3.63 (br s, 2H),2.18 (s, 3H) 184

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- ((3-(3- (dimethyl-amino) propoxy)-4- methoxy- phenyl)amino)- 1HNMR (400 MHz, DMSO-d₆): δ9.46 (s, 1H), 8.42 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 8.0 (s, 1H), 7.52(d, J = 2 Hz, 1H), 7.45-7.42 (m, 2H), 7.33 (m, 2H), 7.29-7.27 (m, 1H),7.16-7.13 (m, 1H),  3 5-methyl- 6.86 (d, J = 8.8 Hz, pyrimidin-4- 1H),6.8-6.79 (m, yl)-1H- 1H), 5.06-5.01 (m, pyrrole-3- 1H), 4.93 (br s,carboxamide 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.69 (s, 3H), 3.65 (br s,3H), 2.32-2.30 (m, 2H), 2.27 (s, 3H), 2.1 (s, 6H), 1.84- 1.77 (m, 2H)185

1-(2-((2,3- dihydrobenzo- furan-6-yl) amino)-5- methyl- pyrimidin-4-yl)-N-(2- hydroxy-1- phenylethyl)- 1H-pyrrole- 3-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.57 (s, 1H), 8.44 (s, 1H), 8.22 (d, J = 8 Hz, 1H),8.00 (s, 1H), 7.42 (s, 1H), 7.37- 7.28 (m, 5H), 7.22- 7.19 (m, 1H),7.13- 7.07 (m, 2H), 6.79 (s, 1H), 5.05 (m, 1H), 4.86 (t, J = 4 Hz, 1H),4.48 (t, J = 8.4 Hz, 2H),  3 3.65 (m, 2H), 3.08 (t, J = 8.4 Hz, 2H),2.30 (s, 3H) 186

1-(2-(chroman- 7-ylamino)-5- methyl- pyrimidin-4- yl)-N-(2- hydroxy-1-phenylethyl)- 1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.51(s, 1H), 8.44 (s, 1H), 8.22 (d, J = 8 Hz, 1H), 8.00 (s, 1H), 7.42 (t, J= 2.4 Hz, 1H), 7.37-7.35 (m, 2H), 7.30-7.28 (m, 2H), 7.22-7.21 (m, 2H),7.14-7.12 (m, 1H), 6.91 (d, J = 8 Hz, 1H), 6.79 (br s, 1H), 5.07-5.02(m, 1H), 4.86 (t, J =  3 6 Hz, 1H), 4.07 (t, J = 4.8 Hz, 2H), 3.67-3.62(m, 2H), 2.64 (t, J = 8 Hz, 2H), 2.30 (s, 3H), 1.87 (t, J = 4 Hz, 2H),1.21 (s, 2H) 187

N-(2-hydroxy- 1-(m-tolyl) ethyl)-1-(5- methyl-2- (((S)-tetra-hydrofuran- 3-yl)amino) pyrimidin-4- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.27 (s, 1H), 8.15 (d, J = 8 Hz, 1H), 7.94(s, 1H), 7.43 (d, J = 4 Hz, 1H), 7.38 (s, 1H), 7.19-7.12 (m, 3H), 7.01(d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 5.02-4.97 (q, J = 8 Hz, 1H),  34.84-4.81 (t, J = 4 Hz, 1H), 4.36-4.35 (m, 1H), 3.89-3.78 (m, 2H),3.72-3.63 (m, 3H), 3.54-3.51 (m, 1H), 2.27 (s, 3H), 2.22 (s, 3H),2.17-2.08 (m, 1H), 1.90-1.82 (m, 1H) 188

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- ((tetrahydro-furan-3- yl)amino) pyridin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 8.18 (d, J = 8 Hz, 1H), 8.02 (d, J = 5.6 Hz, 1H), 7.97(s, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 7.33-7.28 (m, 3H), 6.87 (d, J = 8Hz, 1H), 6.78 (d, J = 4.4 Hz, 1H), 6.74 (s, 1H), 13 6.61 (s, 1H), 5.04-5.01 (m, 1H), 4.94- 4.91 (m, 1H), 4.40 (br s, 1H), 3.91- 3.81 (m, 2H),3.79- 3.67 (m, 3H), 3.52- 3.46 (m, 1H), 2.20- 2.12 (m, 1H), 1.78- 1.77(m, 1H) 189

N-(2-hydroxy- 1-phenylethyl)- 1-(2-((tetra- hydrofuran-3- yl)amino)pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ8.13 (d, J = 8 Hz, 1H), 8.02 (d, J = 5.6 Hz, 1H), 7.97 (s, 1H), 7.35 (d,J = 7.2 Hz, 3H), 7.29 (t, J = 6.8 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H),6.87 (d, J = 6.8 Hz, 1H), 6.78 (d, J = 13 5.2 Hz, 1H), 6.74 (s, 1H),6.60 (s, 1H), 5.05-5.02 (m, 1H), 5.0-4.85 (m, 1H), 4.38 (br s, 1H),3.88-3.83 (m, 2H), 3.79-3.64 (m, 3H), 3.54-3.51 (m, 1H), 2.20-2.12 (m,1H), 1.80-1.75 (m, 1H) 190

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-(((tetrahydro- furan-2-yl) methyl)- amino) pyrimidin-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.24 (d, J = 6.4 Hz, 2H), 7.95 (s, 1H), 7.41 (s, 2H),7.35-7.32 (m, 2H), 7.27 (d, J = 6.4 Hz, 1H), 7.14 (s, 1H), 6.65 (s, 1H),5.05-5.03 (m, 1H), 4.92 (t,  3 yl)-1H- J = 6 Hz, 1H), pyrrole-3-3.98-3.94 (m, 1H), carboxamide 3.75-3.7 (m, 1H), 3.67-3.58 (m, 3H),3.4-3.34 (m, 2H), 2.21 (s, 3H), 1.88- 1.61 (m, 3H), 1.61- 1.56 (m, 1H)191

N-(2-amino- 1-phenylethyl)- 1-(2-((4- fluorophenyl)- amino)-5- methyl-pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.14 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.97(s, 1H), 7.61 (t, J = 8.4 Hz, 2H), 7.37-7.29 (m, 4H), 7.24-7.22 (m, 1H),7.11-7.06 (m, 2H), 6.72 (s, 1H), 4.98 (d, J = 5.2 Hz, 1H), 3.06-2.93 11(m, 2H), 2.09 (s, 3H). 192

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-(((S)-tetra- hydrofuran-3- yl)amino) pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.38 (t, J = 8.4 Hz, 2H) 8.29 (s, 1H), 8.11(s, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J = 15.6 Hz,3H), 5.02 (d, J = 5.2 Hz, 2H), 4.34 (s, 1H), 3.87- 3.78 (m, 2H), 3.72- 6 carboxamide 3.67 (m, 3H), 3.55- 3.28 (m, 1H), 2.19 (s, 3H), 2.19-2.08(m, 1H), 1.89-1.85 (m, 1H) 193

N-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((pyridin-3- ylmethyl)- amino) pyridin-4-yl)- 1H-pyrrole- 1HNMR (400MHz, DMSO-d₆): δ 8.53 (s, 1H), 8.40 (s, 1H), 8.10 (d, J = 8 Hz, 1H),7.94 (s, 1H), 7.69 (d, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 2H), 7.33 (t, J= 8 Hz, 3H), 7.14 (s, 1H), 7.01 (s, 1H), 6.69 (s, 1H), 11, 63-carboxamide 6.43 (s, 1H), 5.01 (d, J = 8 Hz, 1H), 4.91 (s, 1H), 4.50(d, J = 8 Hz, 2H), 3.63 (d, J = 4 Hz, 2H), 2.04 (s, 3H) 194

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1- (2-((3- (dimethyl-carbamoyl)-4- fluorophenyl) amino)-5- methyl- pyrimidin-4- 1HNMR (400MHz, DMSO-d₆): δ 9.82 (s, 1H), 8.48 (s, 1H), 8.26 (d, J = 8 Hz, 1H),8.01 (s, 1H), 7.74-7.72 (m, 2H), 7.44 (d, J = 4.8 Hz, 2H), 7.34-7.29 (m,2H), 7.28-7.27 (m, 1H), 7.20-7.18 (m, 1H), 6.79 (s, 1H),  3 yl)-1H-5.06-5.01 (m, 1H), pyrrole-3- 4.93 (t, J = 5.2 Hz, carboxamide 1H),3.68-3.63 (m, 2H), 2.96 (s, 3H), 2.85 (s, 3H), 2.32 (s, 3H) 195

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (cyclohexyl- amino)-5-methyl- pyrimidin-4- yl)-1H- pyrrole-3- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.23 (s, 1H), 7.94 (s, 1H), 7.41 (s, 1H), 7.35- 7.28 (m,4H), 7.04 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 5.05- 5.01 (m, 1H), 4.91(t, J = 5.6 Hz, 1H), 3.71-3.59 (m, 3H), 2.2 (s, 3H), 1.87-  3 1.84 (m,2H), 1.68- 1.55 (m, 3H), 1.3- 1.12 (m, 6H) 196

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2- ((4-(methyl-carbamoyl) phenyl)amino) pyrimidin-4- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 9.94 (s, 1H), 8.52 (s, 1H), 8.29 (d, J = 8.4Hz, 1H), 8.2 (d, J = 4 Hz, 1H), 8.04 (s, 1H), 7.8-7.75 (m, 4H), 7.47 (s,1H), 7.43 (s, 1H), 7.33- 7.29 (m, 3H), 6.81 (s, 1H), 5.04 (d, J = 6.8Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H),  3 3.66 (d, J = 5.2 Hz, 2H), 2.74 (d,J = 4 Hz, 3H), 2.34 (s, 3H) 197

1-(2-(sec- butylamino)- 5-methyl- pyrimidin-4- yl)-N-((S)- 1-(3-chloro-4-fluoro- phenyl)-2- hydroxy- ethyl)-1H- pyrrole-3- carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 8.22 (d, J = 7.6 Hz, 2H), 7.93 (s, 1H), 7.55 (d, J= 7.2 Hz, 1H), 7.33 (t, J = 8.8 Hz, 3H), 6.99 (d, J = 4 Hz, 1H), 6.72(s, 1H), 5.04-4.99 (m, 1H), 4.92 (t, J = 5.6 Hz, 1H), 3.84 (t, J = 6.8Hz, 1H),  3 3.66-3.61 (m, 2H), 2.20 (s, 3H), 1.56- 1.42 (m, 2H), 1.09(d, J = 6.4 Hz, 3H), 0.84 (t, J = 7.6 Hz, 3H) 198

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((2-oxoindolin-5- yl)amino) pyrimidin-4- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 10.2 (s, 1H), 9.48 (s, 1H), 8.4 (s, 1H),8.29 (d, J = 8 Hz, 1H), 8.04 (s, 1H), 7.6 (s, 1H), 7.46-7.42 (m, 3H),7.34-7.26 (m, 3H), 6.77 (s, 1H), 6.72 (d, J = 12 Hz, 1H), 5.06-5.01 (m,1H), 4.93 (t, J = 8 Hz, 1H), 3.67-3.62 (m, 2H), 3.45 (s, 2H),  3 2.29(s, 3H) 199

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2- ((1-methyl-piperidin-3- yl)-amino) pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR (400 MHz,DMSO-d₆): δ 8.25 (s, 2H), 7.95 (s, 1H), 7.41 (s, 1H), 7.37- 7.26 (m,4H), 7.01 (s, 1H) 6.73 (s, 1H), 5.02 (d, J = 4 Hz, 1H), 4.94 (s, 1H),3.87 (br s, 1H), 3.64 (d, J = 4 Hz, 2H), 2.21 (s, 3H),  3 carboxamide2.14 (s, 3H), 1.88- 1.78 (m, 4H), 1.63- 1.48 (m, 4H) 201

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2- ((tetrahydro-2H-pyran-4- yl)-amino) pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.41 (d, J = 7.8 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.09(s, 1H), 7.42 (s, 1H), 7.38 (d, J = 9.6 Hz, 1H), 7.32-7.27 (m, 3H),5.05-4.98 (m, 2H), 3.85-3.77 (m, 3H), 3.71 (t, J = 4 Hz,  6 carboxamide2H), 3.38 (t, J = 8 Hz, 2H), 2.16 (s, 3H), 1.80 (d, J = 11.2 Hz, 2H),1.51- 1.44 (m, 2H) 202

N-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1-(2- ((2-hydroxy-cyclohexyl) amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 8.24 (t, J = 8.4 Hz, 2H), 7.94 (s, 1H), 7.55 (d, J = 7.2 Hz,1H), 7.35 (d, J = 7.6 Hz, 3H), 6.89 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H),5.01 (d, J = 7.2 Hz, 1H), 4.96 (m, 1H),  3 pyrrole-3- 4.53 (d, J = 4.4Hz, carboxamide 1H), 3.64-3.55 (m, 4H), 2.20 (s, 3H), 1.93-1.85 (m, 2H),1.60 (br s, 2H), 1.31-1.18 (m, 4H) 203

N-(1-(3- chloro-4- fluorophenyl)- 2-hydroxy- ethyl)-1-(2- ((1-(hydroxy-methyl) cyclopropyl) amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR (400MHz, DMSO-d₆): δ 8.23 (t, J = 12.4 Hz, 2H), 7.92 (s, 1H), 7.55 (d, J =6.4 Hz, 1H), 7.37 (t, J = 13.2 Hz, 4H), 6.74 (s, 1H), 5.00 (s, 1H), 4.93(s, 1H), 4.62 (s, 1H), 3.63 (s, 2H), 3.52 (s, 2H), 2.24 (s, 3H), 0.75(s, 2H), 0.62  3 pyrrole-3- (s, 2H) carboxamide 204

N-(1-(4- fluoro-phenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2- (((S)-tetra-hydro-furan- 3-yl)amino)- pyrimidin-4- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.27 (s, 1H), 8.19 (d, J = 8 Hz, 1H), 7.94(s, 1H), 7.44-7.38 (m, 4H), 7.11 (t, J = 8.8 Hz, 2H), 6.74 (s, 1H), 5.02(d, J = 7.2 Hz, 1H), 4.87 (t, J = 5.6 Hz, 1H), 4.34 (s, 1H), 3.86 (t, J= 8 Hz, 1H),  3 3.80 (t, J = 7.6 Hz, 1H), 3.72-3.68 (m, 3H), 3.54-3.52(m, 1H), 2.22 (s, 3H), 2.15-2.10 (m, 1H), 1.86 (d, J = 5.6 Hz, 1H) 205

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((4-morpholino- phenyl)amino) pyrimidin-4- yl)-1H- pyrrole-3- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.40 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.01(s, 1H), 7.56 (d, J = 9.2 Hz, 2H), 7.43 (s, 2H), 7.36-7.27 (m, 3H), 6.88(d, J = 8.8 Hz, 2H), 6.78 (s, 1H), 5.04 (d, J = 6.8 Hz, 1H), 4.94 (t, J= 11.2 Hz, 1H), 3.71 (t, J = 4 Hz, 4H), 3.68-3.64 (m, 2H), 3.01 (t, J =4.8 Hz, 4H), 2.29 (s, 3H)  3 206

N-(2-amino- 1-phenylethyl)- 1-(2-((4- fluorophenyl)- amino)pyridin-4-yl)- 1H-pyrrole- 3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.19 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 6 Hz, 1H), 7.98 (d,J = 9.6 Hz, 3H), 7.67-7.63 (m, 2H), 7.46 (s, 1H), 7.42-7.36 (m, 4H),7.31 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 8.8 Hz, 2H), 7.03 (d, J = 5.2 Hz,1H),  7, 4 6.91 (s, 1H), 6.79 (s, 1H), 5.34-5.30 (m, 1H), 3.22 (s, 2H).207

N-((S)-2- hydroxy-1- (6-methyl- pyridin-2-yl) ethyl)-1-(5- methyl-2-(((S)-tetra- hydrofuran-3- yl)amino) pyrimidin-4- yl)-1H- 1HNMR (400MHz, DMSO-d₆): δ 8.28 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H),7.60 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 7.40 (s, 1H), 7.16(d, J = 7.2 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 6.76 (s, 1H),  3 pyrrole-3-5.07-5.02 (m, 1H), carboxamide 4.84 (t, J = 5.6 Hz, 1H), 4.36 (s, 1H),3.89-3.79 (m, 3H), 3.75-3.69 (m, 2H), 3.67-3.51 (m, 1H), 2.45 (s, 3H),2.24 (s, 3H), 2.18-2.09 (m, 1H), 1.90-1.85 (m, 1H) 208

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((1-methyl- pyrrolidin-3- yl)amino) pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.27 (d, J = 9.2 Hz, 2H), 7.97(s, 1H), 7.40 (d, J = 8.8 Hz, 3H), 7.34-7.32 (m, 2H), 7.27 (d, J = 8.0Hz, 3H), 6.76 (s, 1H), 5.05-5.00 (m, 1H), 4.94 (t, J = 6 Hz, 1H),4.36-4.34 (m, 1H), 3.66 (d, J =  3 4.4 Hz, 2H), 3.00 (br s, 1H), 2.77(s, 1H), 2.67 (d, J = 13.2 Hz, 1H), 2.58 (br s, 1H), 2.48 (s, 3H), 2.23(s, 3H) 209

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((3- (1,2,3,6-tetrahydro- pyridin-4-yl)- 1H-indol-5- yl)amino)- 1HNMR (400 MHz,DMSO-d₆): δ 11.17 (s, 1H), 9.49 (s, 1H), 8.95 (s, 1H), 8.43- 8.39 (m,2H), 8.33 (s, 1H), 8.07 (s, 1H), 7.46-7.42 (m, 3H), 7.32-7.31 (m, 5H),6.84 (s, 1H), 6.06 (s, 1H), 5.03 (s, 1H),  3 pyrimidin-4- 3.68-3.66 (d,J = 8 yl)-1H- Hz, 3H), 3.3 (s, 1H), pyrrole-3- 2.70-2.65 (m, 3H),carboxamide 2.31 (s, 3H) hydrochloride 211

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.39 (d, J = 8 Hz, 1H), 8.34 (s, 1H), 8.28(s, 1H), 8.09 (s, 1H), 7.43 (s, 1H), 7.37- 7.32 (m, 3H), 7.29 (br s,1H), 5.02 (d, J = 8 Hz, 2H), 3.85- 3.82 (br s, 3H), 3.72 (t, J = 8 Hz, 6 carboxamide 2H), 3.39-3.26 (m, 2H), 2.17 (s, 3H), 1.81 (d, J = 8 Hz,2H), 1.48 (d, J = 8 Hz, 2H). 212

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-N- methyl-1-(5- methyl-2-(((S)-tetra- hydrofuran- 3-yl)amino)- pyrimidin-4- yl)-1H- 1HNMR (400MHz, DMSO-d₆): δ 8.26 (s, 1H), 7.68 (s, 1H), 7.40-7.33 (m, 5H), 7.26 (s,1H), 6.51 (s, 1H), 5.56 (br s, 1H), 5.07 (s, 1H), 4.31 (s, 1H), 3.99-3.78 (m, 4H), 3.71- 3.66 (m, 1H), 3.53- 351 (m, 1H), 2.90  3 pyrrole-3-(br s, 3H), 2.18- carboxamide 2.08 (m, 4H), 1.86- 1.84 (m, 1H) 213

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((4-fluoro-3-(piperazin- 1-yl)phenyl) amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR(400 MHz, DMSO-d₆): δ 9.63 (s, 1H), 8.46 (s, 1H), 8.29 (d, J = 8.0 Hz,1H), 8.05 (s, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 11.2 Hz, 2H),7.33- 7.22 (m, 4H), 7.06- 7.00 (t, J = 12.4 Hz, 1H,), 6.81 (s, 1H),  3pyrrole-3- 5.04 (d, J = 7.2 Hz, carboxamide 1H), 3.70-3.60 (m, 2H), 2.97(d, J = 12 Hz, 8H), 2.32 (s, 3H) 214

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2- (piperidin-4-ylamino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.38 (d, J = 8.4 Hz, 2H), 8.30 (s, 1H), 8.11 (s, 1H), 7.9(br s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.32- 7.29 (m, 3H), 5.03- 5.02(m, 2H), 3.96 (s, 1H), 3.72 (t, J = 5.2 Hz, 2H), 2.93 (s, 3H), 2.19 (s,3H),  6 1.9 (s, 3H), 1.60 (d, J = 8 Hz, 2H) 215

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((4-(piperidin-4- yl)phenyl) amino) pyrimidin-4- yl)-1H- pyrrole-3-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.45 (s, 1H), 8.32(d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 8 Hz, 2H), 7.43 (s, 2H),7.31 (d, J = 16 Hz, 3H), 7.14 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H),5.04-4.99 (m, 2H), 3.67 (s, 2H), 3.49 (s, 4H), 2.97 (t, J = 12 Hz, 2H),2.31 (s, 3H), 1.90 (d, J = 12.8 Hz, 2H), 1.76 (d, J = 12.8 Hz, 2H)  3216

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- ((3-fluoro-4-(piperidin-4- yl)phenyl) amino)-5- methyl- pyrimidin-4- yl)-1H-pyrrole-3- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.49(s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J = 14 Hz,1H), 7.44-7.42 (m, 3H), 7.32-7.28 (m, 3H), 7.15 (t, J = 8.8 Hz, 1H),6.81 (s, 1H), 5.04-5.02 (m, 1H), 4.96-4.93 (m, 1H), 3.65 (s, 2H),3.3-3.27 (m, 2H) 3.02-2.99 (m, 4H), 2.32 (s, 3H), 1.84- 1.79 (m, 4H)  3217

(R)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.37 (d, J = 12.0 Hz, 2H), 8.27 (s, 1H),8.08 (s, 1H), 7.42 (s, 1H), 7.36-7.27 (m, 4H), 5.02-5.00 (m, 2H),3.84-3.81 (m, 3H), 3.71 (t, J = 5.6 Hz, 2H), 3.38- 3.30 (m, 2H), 2.16  6carboxamide (s, 3H), 1.80 (d, J = 12 Hz, 2H), 1.51- 1.44 (m, 2H) 218

N-((R)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (((S)-1-hydroxy-butan-2-yl) amino)-5- methyl- pyrimidin-4- yl)-1H- pyrrole-3- 1HNMR (400MHz, DMSO-d₆): δ 8.23 (d, J = 6.8 Hz, 2H), 7.93 (s, 1H), 7.41 (s, 1H),7.37 (s, 1H), 7.33-7.25 (m, 3H), 6.78 (d, J = 8 Hz, 1H), 6.73 (s, 1H),5.04-4.99 (m, 1H), 4.91 (t, J = 5.6 Hz, 1H), 4.55 (t, J =  3 carboxamide5.6 Hz, 1H), 3.80 (s, 1H), 3.64 (d, J = 5.2 Hz, 2H), 3.46-3.41 (m, 1H),3.36-3.32 (m, 1H), 2.20 (s, 3H), 1.67- 1.60 (m, 1H), 1.44- 1.37 (m, 1H),0.85 (t, J = 8 Hz, 3H) 219

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (((S)-1- hydroxy-butan-2-yl) amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 8.24 (d, J = 6.8 Hz, 1H), 7.94 (s, 1H), 7.52 (s, 1H),7.40-7.27 (m, 5H), 6.79-6.77 (d, J = 8 Hz, 1H), 6.73 (s, 1H), 5.02- 5.01(m, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.55 (t, J = 5.6 Hz,  3 pyrrole-3-1H), 3.82 (d, J = carboxamide 4.8 Hz, 2H), 3.64 (d, J = 5.2 Hz, 1H),3.42-3.27 (m, 2H), 2.2 (s, 3H), 1.64- 1.62 (m, 1H), 1.42- 1.40 (m, 1H),0.85 (t, J = 8 Hz, 3H). 220

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (((S)-1- hydroxy-butan-2-yl) amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 8.38 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 14.8 Hz, 2H), 8.08(s, 1H), 7.42 (s, 1H), 7.31- 7.28 (m, 3H), 6.96 (d, J = 8 Hz, 1H),5.03-4.98 (m, 2H), 4.55 (br s, 1H), 3.80 (br s, 1H),  6 imidazole-4-3.72-3.70 (m, 2H), carboxamide 3.45-3.41 (m, 2H), 2.17 (s, 3H), 1.65-1.60 (m, 1H), 1.44- 1.40 (m, 1H), 0.851 (t, J = 8 Hz, 3H) 221

N-(2-amino- 1-phenylethyl)- 1-(2-((4- fluorophenyl)- amino)pyridin-4-yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.19 (s,1H), 8.48 (d, J = 8.4 Hz, 1H), 8.43 (s, 1H), 8.22-8.20 (m, 2H),7.65-7.62 (m, 2H), 7.35-7.28 (m, 4H), 7.23-7.19 (m, 1H), 7.15-7.07 (m,3H), 6.96 (s, 1H), 4.97 (s, 1H), 3.01-3.0 (m, 1H), 2.92-2.90 (m, 1H) 11222

1-(2-((4- fluorophenyl) amino)-5- methylpyridin- 4-yl)-N-(2- hydroxy-1-phenylethyl)- 1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ9.13 (s, 1H), 8.24 (d, J = 8 Hz, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.97(s, 1H,) 7.67- 7.59 (m, 2H) 7.36 (d, J = 7.6 Hz, 2H), 7.29 (t, J = 7.6Hz, 2H), 7.22 (t, J = 6.8 Hz, 1H,), 7.08 (t, J = 3.2 Hz, 2H), 6.72 (s,1H) 5.03- 11 4.96 (m, 2H), 3.69 (br s, 2H), 2.08 (s, 3H) 223

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- ((4-fluoro-3-morpholino- phenyl)amino)- 5-methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H), 8.53 (s, 1H), 8.42(d, J = 7.6 Hz, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.52 (d, J = 7.6 Hz,2H), 7.54 (d, J = 8 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 7.32 (s, 1H),7.27 (d, J = 3.2 Hz, 1H), 7.21  6 (d, J = 7.6 Hz, 1H), 7.06-7.01 (m,1H), 5.02 (t, J = 4.8 Hz, 2H), 3.70 (s, 6H), 2.96 (s, 4H), 2.27 (s, 3H)225

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(5-methyl- 2-((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.53 (d, J = 8 Hz, 1H), 8.32 (s, 1H), 8.25(s, 1H), 8.06 (s, 1H), 7.40-7.27 (m, 6H), 4.91 (s, 1H), 3.83- 3.81 (m,4H), 3.47- 3.26 (m, 3H), 2.95- 2.88 (m, 2H), 2.16 (s, 3H), 1.79 (d, J = 4 8 Hz, 2H), 1.48- 1.45 (m, 2H) 225a

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.58 (d, J = 6.8 Hz, 1H), 8.33 (s, 1H), 8.27(s, 1H), 8.07 (s, 1H), 7.41 (s, 1H), 7.36- 7.28 (m, 4H), 4.97 (br s,1H), 3.84- 3.82 (m, 3H), 3.38- 3.33 (m, 2H), 3.01- 2.94 (m, 2H), 2.16 4, 20 carboxamide, (s, 3H), 1.80 (d, J = Enantiomer #1 11.6 Hz, 2H),1.52- 1.44 (m, 2H). 225b

(R)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.58 (d, J = 8 Hz, 1H), 8.33 (s, 1H), 8.27(s, 1H), 8.07 (s, 1H), 7.42 (s, 1H), 7.36- 7.27 (m, 4H), 5.02- 4.91 (m,1H), 3.84- 3.82 (m, 3H), 3.35 (m, 2H), 3.05-2.91 (m, 2H), 2.16 (s,  4carboxamide, 3H), 1.79 (d, J = Enantiomer #2 11.6 Hz, 2H), 1.51- 1.4 (m,2H). 226

N-(1-(3- chloro-phenyl)- 2-hydroxy- ethyl)-1-(2- (cyclohexyl- amino)-5-methyl- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.38 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.07(s, 1H), 7.42 (s, 1H), 7.34- 7.27 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H),5.04-4.97 (m, 2H), 3.71 (t, J = 5.6 Hz, 2H), 2.15 (s, 3H),  6 1.85 (d, J= 7.2 Hz, 2H), 1.67 (s, 2H), 1.55 (d, J = 12 Hz, 1H), 1.28-1.20 (m, 6H)227

N-(2-amino-1- phenylethyl)- 1-(2-((4- fluorophenyl)- amino)-5- methyl-pyridin-4-yl)- 1H-imidazole- 4-carboxamide, Enantiomer #1 1HNMR (400MHz, DMSO-d₆): δ 9.14 (s, 1H), 8.5 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H),8.08 (s, 1H), 7.97 (s, 1H), 7.63- 7.59 (m, 2H), 7.37- 7.30 (m, 4H), 7.23(t, J = 6.8 Hz, 1H), 7.08 (t, J = 8.4 Hz, 2H), 6.71 (s, 1H), 5.03-5.02(m, 1H), 4.0 (br s, 2H), 3.11- 11 3.06 (t, J = 12.0 Hz, 1H), 2.96-2.94(m, 1H), 2.08 (s, 3H) 228

N-(2-amino-1- phenylethyl)- 1-(2-((4- fluorophenyl)- amino)-5- methyl-pyridin-4-yl)- 1H-imidazole- 4-carboxamide, Enantiomer #2 1HNMR (400MHz, DMSO-d₆): δ 9.13 (s, 1H), 8.50 (d, J = 4 Hz, 1H), 8.15 (s, 1H),8.08 (s, 1H), 7.98 (s, 1H), 7.63- 7.59 (m, 2H), 7.37- 7.30 (m, 4H), 7.24(t, J = 6.8 Hz, 1H), 7.08 (t, J = 8.0 Hz, 2H), 6.71 (s, 1H), 5.02 (m,1H), 3.11- 3.06 (t, J = 12 Hz, 11 1H), 2.96-2.94 (m, 1H), 2.08 (s, 3H)229

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- fluoro-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- pyrrole-3-1HNMR (400 MHz, DMSO-d₆): δ 8.47 (d, J = 4 Hz, 1H), 8.39 (d, J = 8 Hz,1H), 8.14 (s, 1H), 7.56 (s, 1H), 7.41 (s, 2H), 7.33-7.26 (m, 3H), 6.81(s, 1H), 5.04-4.99 (m, 1H), 4.92 (t, J = 8 Hz, 1H), 3.83 (d,  3carboxamide J = 12 Hz, 3H), 3.66-3.59 (m, 2H), 3.38 (t, J = 12 Hz, 2H),1.83-1.80 (d, J = 12 Hz, 2H), 1.54-1.45 (m, 2H) 230

N-(2-amino- 1-(4-fluoro- phenyl)ethyl)- 1-(2-((4- fluoro-phenyl)amino)-5- methyl- pyridin-4-yl)- 1H-imidazole- 4-carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.13 (s, 1H), 8.58 (d, J = 8 Hz, 1H), 8.15 (s, 1H),8.08 (s, 1H), 7.98 (s, 1H), 7.63- 7.59 (m, 2H), 7.41 (t, J = 8.4 Hz,2H), 7.15 (t, J = 8.8 Hz, 2H), 7.08 (t, J = 8.8 Hz, 2H), 6.71 (s, 1H),5.08 (s, 1H), 3.13 (s, 2H), 2.98 11 (d, J = 10 Hz, 2H), 2.07 (s, 3H) 231

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(5-methyl- 2-((4-phenoxy-phenyl)amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.78 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 5.54 (s, 1H),8.36 (s, 1H), 8.19 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H),7.39- 7.31 (m, 5H), 7.06 (t, J = 8 Hz, 1H), 6.99-6.92 (m, 4H), 5.24 (brs, 1H), 4.11 (s, 1H), 3.17 (br s, 1H), 2.25 (s, 3H), 0.85 (t, J = 8 Hz, 4 2 H) 232

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(2-((2- chloro-4-fluorophenyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.89 (d, J = 4.5Hz, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.82 (br s, 2H),7.66-7.62 (m, 1H), 7.50-7.47 (m, 2H), 7.40-7.36 (m, 3H), 7.21-7.18 (m,1H), 5.30 (d, J = 2.5 Hz, 1H),  4 3.42-3.32 (m, 1H), 3.27-3.19 (m, 1H),2.24 (s, 3H) 233

N-(2-hydroxy- 1-(thiophen-2- yl)ethyl)-1-(5- methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.23 (t, J = 6.0 Hz, 2H), 8.11(s, 1H), 7.35 (t, J = 6.8 Hz, 2H), 7.02 (s, 1H), 6.94 (t, J = 4.4 Hz,1H), 5.30- 5.25 (m, 1H), 5.12 (t, J = 5.6 Hz, 1H), 3.9 (br s, 1H),  63.83 (d, J = 10.8 Hz, 2H), 3.77 (t, J = 5.2 Hz, 2H), 3.36 (t, J = 10.8Hz, 2 H), 2.16 (s, 3H), 1.81 (d, J = 12 Hz, 2H), 1.51- 1.44 (m, 2H). 234

N-(2-hydroxy- 1-(thiophen-3- yl)ethyl)-1- (5-methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.25 (s, 1H), 8.14 (d, J = 8.8Hz, 1H), 8.09 (s, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.42-7.32 (m, 2H), 7.13(d, J = 4.8 Hz, 1H), 5.15-5.10 (m, 1H), 4.95 (t, J = 5.6 Hz, 1H), 3.88 6 (br s, 1H), 3.83 (d, J = 10.8 Hz, 2H), 3.75-3.68 (m, 2H), 3.36 (t, J= 11.2 Hz, 2H), 2.16 (s, 3H), 1.81 (d, J = 11.6 Hz, 2H), 1.53-1.43 (m,2H). 235

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(5-methyl- 2-((tetra-hydrofuran- 3-yl)amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.87 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 8.30(s, 1H), 8.15 (s, 1H), 7.60 (br s, 1H), 7.50 (s, 1H), 7.41-7.33 (m, 3H),5.28 (s, 1H), 4.34 (s, 1H), 4.34-3.84 (m, 2H), 3.81-3.71 (m, 1H),  43.68-3.53 (m, 1H), 3.36-3.27 (m, 1H), 3.33-3.19 (m, 1H), 2.99-2.93 (m,1H), 2.18 (s, 3H), 1.90- 1.82 (m, 1H). 236

N-(2-amino- 1-(3-chloro- 5-fluoro- phenyl)ethyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.57 (d, J = 7.2 Hz, 1H), 8.33(s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.34 (br s, 1H), 7.27 (br s, 1H),7.18 (d, J = 10 Hz, 1H), 4.91 (s, 1H), 3.84-3.81 (m, 3H), 3.38-3.27 (m,2H), 2.93 (s, 1H), 2.87 (s, 1H), 2.30 (s, 3H), 1.83-  4 1.78 (m, 2H),1.49 (br s, 2H) 237

N-(2-hydroxy- 1-(3-(trifluoro- methyl)- phenyl)ethyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.49 (d, J = 8.0 Hz, 1H), 8.33 (s, 1H), 8.27(s, 1H), 8.08 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 12 Hz, 1H), 7.59-7.51(m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 5.12-5.03 (m, 2H), 3.89 (br s, 1H), 3 carboxamide 3.83 (d, J = 11.6 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.35(t, J = 10.4 Hz, 2H), 2.16 (s, 3H), 1.80 (d, J = 11.2 Hz, 2H), 1.52-1.42(m, 2H) 238

N-(2-hydroxy- 1-(m-tolyl) ethyl)-1-(5- methyl-2- ((tetrahydro-2H-pyran-4- yl)amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 8.26 (s, 1H), 8.20 (d, J = 8.4Hz, 1H), 8.07 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.19-7.12 (m, 3H), 7.02(d, J = 7.2 Hz, 1H), 4.93-4.96 (m, 2H), 3.83 (d, J = 10.8 Hz, 3H),  33.67 (d, J = 4.8 Hz, 2H), 3.35 (t, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.81(d, J = 12.8 Hz, 2H)), 1.52-1.43 (m, 2H). 239

1-{5-Methyl- 2-[1-(tetra- hydro-pyran- 4-yl)-ethyl- amino]- pyrimidin-4-yl}-1H- pyrrole-3- carboxylic acid [(S)-1- (3-chloro- phenyl)-2- 1HNMR(400 MHz, DMSO-d₆): δ 8.38 (d, J = 8.0 Hz, 2H), 8.30 (s, 1H), 8.26 (s,1H), 8.07 (s, 1H), 7.42 (s, 1H), 7.31- 7.23 (m, 2H), 5.02 (s, 2H), 3.83(d, J = 5.2 Hz, 2H), 3.71 (t, J = 5.2 Hz, 3H), 3.32-3.16 (m, 2H), 2.16(s, 3H), 1.58 17, 6 hydroxy- (t, J = 10.4 Hz, 3H), ethyl]-amide 1.07 (d,J = 6.8 Hz, 3H) 240

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((4,4-difluorocyclo- hexyl)amino)- 5-methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.38 (d, J = 7.6 Hz, 1H), 8.34(s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.42 (br s, 2H), 7.31 (s, 2H), 7.28(s, 1H), 5.01 (d, J = 4.8 Hz, 2H), 3.91 (br s, 1H), 3.71 (t, J = 5.6 Hz,2H), 2.04-1.98 (m, 2H), 1.89 (d, J =  4, 6 10.8 Hz, 2H), 1.58- 1.55 (m,2H 241

(S)-1-(2-((2- chloro-4- fluorophenyl)- amino)-5- methyl- pyrimidin-4-yl)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.14 (s, 1H), 8.46 (s, 1H), 8.39(d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.67- 7.63 (m, 1H),7.49- 7.46 (m, 1H), 7.42 (s, 1H), 7.34-7.31 (s, 2H), 7.27-7.21 (m, 1H),7.20-7.18 (m, 1H), 5.03-4.97  6 (m, 2H), 3.71 (t, J = 5.6 Hz, 2H), 2.30(s, 3H). 242

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-(((1r,4S)-4-hydroxy- cyclohexyl) amino)-5- methyl- pyrimidin-4- yl)-1H-imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.38 (d, J = 8 Hz,1H), 8.31 (s, 1H), 8.26 (s, 1H), 7.42 (s, 1H), 7.31-7.28 (m, 3H), 7.19(d, J = 7.2 Hz, 1H), 5.02-4.99 (m, 2H), 4.479-4.471 (m, 1H), 3.72-3.71(m, 2H), 3.70 (br, 1H), 3.37-3.36 (m, 1H), 2.15 (s, 3H),  3, 6 1.87-1.79(m, 4H), 1.27-1.19 (m, 4H). 243

N-(2-(2- hydroxy- ethyl)benzyl)- 1-(5-methyl- 2-((tetrahydro-2H-pyran-4- yl)amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.46 (t, J = 6 Hz, 1H), 8.33 (s, 1H), 8.24(s, 1H), 8.09 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 5.2 Hz,1H), 7.16- 7.13 (m, 3H), 4.67 (t, J = 5.2 Hz, 1H), 4.48 (d, J = 6 Hz,  32H), 3.89 (br s, 1H), 3.83 (d, J = 11.2 Hz, 2H), 3.62- 3.57 (m, 2H),3.39- 3.32 (m, 2H), 2.82 (t, J = 6.8 Hz, 2 H), 2.17 (s, 3H), 1.80 (d, J= 11.2 Hz, 2H), 1.52-1.44 (m, 2H). 245

N-((1s,3s)- 1-(3-chloro- phenyl)-3- hydroxy- cyclobutyl)- 1-(5-methyl-2-((tetrahydro- 2H-4-yl) amino) pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆) δ 8.87 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.48(s, 1H), 7.44 (d, J = 8 Hz, 1H), 7.32 (t, J = 8 Hz, 2H), 7.23 (d, J = 8Hz, 1H), 5.12 (d, J = 6 Hz, 1H), 3.98-3.81 (m, 4H),  6 imidazole-4- 3.35(t, J = 11.2 Hz, carboxamide 2H), 2.92 (b, 2H), 2.38 (b, 2H), 2.15 (s,3H), 1.79 (d, J = 11.6 Hz, 2H), 1.52-1.43 (m, 2H). 246

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- ((1,1-dioxido-tetrahydro- thiophen-3- yl)amino)-5- methyl- pyrimidin-4- yl)-1H-imidazole- 4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.40- 8.39 (m, 2H),8.29 (s, 1H), 8.13 (s, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.42 (s, 1H), 7.31(bs, 2H), 7.28- 7.27 (m, 1H), 5.00 (q, J₁ = 5.6 Hz, J₂ = 7.6 Hz, 2H),3.71 (d, J = 6.0 Hz, 1H), 3.54-3.49 (m, 1H), 3.36-3.27 (m,  4, 6 1H),3.19-3.14 (m, 1H), 2.98-2.95 (m, 1H), 2.47-2.39 (m, 1H), 2.20-2.12 (m,4H), 247

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(2- (chroman-4-ylamino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.39- 8.37 (m, 2H), 8.29 (s, 1H), 8.11 (s, 1H), 7.81 (d, J =8 Hz, 1H), 7.41 (s, 1H), 7.31 (bs, 2H), 7.27- 7.26 (m, 1H), 7.17 (d, J =7.6 Hz, 1H), 6.80 (t, J = 7.6 Hz,  6 carboxamide 1H), 6.74 (d, J = 8.0Hz, 1H), 5.00 (bs, 1H), 5.0 (q, J₁ = 6.0 Hz, J₂ = 7.6 Hz, 1H), 4.28-4.18(m, 2H), 3.71 (d, J = 5.2 Hz, 2H), 2.21 (s, 3H), 2.07-2.03 (m, 2H). 248

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- ((4-fluoro-phenyl)amino)- 5-methyl- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.56 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 8.14(s, 1H), 7.70-7.67 (m, 2H), 7.41 (s, 1H), 7.35-7.26 (m, 3H), 7.11 (t, J= 8.8 Hz, 2H), 4.94-4.88 (m, 1H), 2.98-2.93 (m, 1H), 2.89-2.86 (m, 1H),2.26 (s, 3H)  4 249

(R)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- ((4-fluoro- phenyl)-amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 9.79 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.53 (s,1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.70- 7.67 (m, 2H), 7.41 (s, 1H),7.35-7.32 (m, 2H), 7.30-7.26 (m, 1H), 7.11 (t, J = 8.4 Hz, 2H),4.95-4.90 (m, 1H), 3.00-2.95 (m, 1H),  4 2.90-2.86 (m, 1H), 2.26 (s, 3H)250

N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2- ((4-phenoxy-phenyl)- amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400MHz, DMSO-d₆): δ 9.79 (s, 1H), 8.53 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H),8.34 (s, 1H), 8.16 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.33 (s, 1H),7.35- 7.27 (m, 5H), 7.07- 7.045 (m, 1H), 6.99- 6.92 (m, 4H), 5.03- 4.98(m, 2H), 3.73- 3.70 (m, 2H), 2.30 (s, 3H)  6 251

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((2-methyl- tetrahydro- 2H-pyran-4- yl)amino) pyrimidin-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.34- 8.32 (m, 1H), 8.22- 8.21 (m, 1H), 8.15- 8.14 (d, J =7.6 Hz, 1H), 8.06-8.04 (m, 1H), 7.42 (s, 1H), 7.33-7.30 (m, 2H),7.269-7.260 (m, 1H), 6.984 (br, 1H),  6 yl)-1H- 5.052-5.00 (m, 1H),imidazole-4- 4.82 (s, 1H), 3.81- carboxamide 3.77 (m, 1H), 3.75- 3.66(m, 2H), 3.45- 3.37 (m, 2H), 2.24- 2.18 (m, 3H), 1.92- 1.89 (m, 1H),1.80- 1.75 (m, 2H), 1.51- 1.39 (m, 1H), 1.21 (m, 2H), 1.18-1.15 (m, 1H),1.07-1.05 (m, 1H). 252

N-(1-(3- chlorophenyl)- 2-hydroxy- propyl)-1- (5-methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.43- 8.41 (d, J = 8.8 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 1H),8.05 (s, 1H), 7.43 (s, 1H), 7.36-7.27 (m, 4H), 4.98-4.97 (m, 1H),4.80-4.76 (m, 1H), 4.06-4.01 (m, 1H), 3.84-3.81 (m,  3 carboxamide 3H),3.38-3.27 (m, (isomer #2) 2H), 2.15 (m, 3H), 1.81-1.78 (m, 2H),1.51-1.43 (m, 2H), 1.02 (m, 3H). 253

N-(1-(3- chlorophenyl)- 2-hydroxy- propyl)-1- (5-methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.42 (d, J = 9.2 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 8.05(s, 1H), 7.43 (s, 1H), 7.35- 7.27 (m, 4H), 4.98- 4.97 (m, 1H), 4.80-4.76 (m, 1H), 4.06- 4.0 (m, 1H), 3.84- 3.81 (m, 3H), 3.38-  3carboxamide 3.26 (m, 2H), 2.15 (isomer #1) (s, 3H), 1.81-1.78 (m, 2H),1.51-1.43 (m, 2H), 1.07-1.01 (m, 3H). 254

N-(2-amino- 1-(3-chloro- 5-fluoro- phenyl)ethyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.60 (s, 1H), 8.50(s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.41-7.31 (m, 4H), 7.05 (s, 1H),6.83 (s, 1H), 5.94 (s, 2H), 4.9 (s, 1H), 3.3-2.80 (m, 2H), 2.25 (s, 3H) 3 255

N-((S)-2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2- (((S)-tetra-hydro-furan- 3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400MHz, DMSO-d₆): δ 8.53 (d, J = 2.8 Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H),8.09 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.34-7.25 (m, 3H), 4.93-4.85(m, 1H), 4.34 (s, 1H), 3.86-3.81 (m, 2H), 3.71-3.67 (m, 20 carboxamide1H), 3.52-3.27 (m, 1H), 2.97-2.92 (m, 1H), 2.89-2.84 (m, 1H), 2.18 (s,3H), 2.07-1.94 (m, 1H), 1.84-1.75 (m, 1H), 1.86 (br s, 2H) 256

N-(2-amino- 1-(3-chloro- phenyl)ethyl)- 1-(2-((4- fluoro-3- morpholino-phenyl) amino)-5- methyl- pyrimidin-4- yl)-1H- 1HNMR (400 MHz, DMSO-d₆)δ 9.73 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 8.35 (s, 1H),8.16 (s, 1H), 7.54 (d, J = 6.4 Hz, 1H), 7.41 (s, 1H), 7.35- 7.20 (m,4H), 7.06- 7.01 (m, 1H), 4.94- 4.89 (m, 1H), 3.70  3 imidazole-4- (s,4H), 2.97 (s, 5H), carboxamide 2.90-2.85 (m, 1H), 2.27 (s, 3H) 257

N-(1-(5- chlorothio- phen-2-yl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- 1HNMR (400MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H),7.36 (d, J = 7.2 Hz, 1H), 6.93- 6.87 (m, 2H), 5.24- 5.17 (m, 2H), 3.84-3.75 (m, 5H), 3.38- 3.27 (m, 2H), 2.16 (s, 3H), 1.88-1.79  3imidazole-4- (m, 2H), 1.51-1.44 carboxamide (m, 2H). 258

N-(1-(3-(tert- butyl)phenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.25 (d, J = 8 Hz, 2H), 8.07(s, 1H), 7.39-7.34 (m, 2H), 7.23-7.19 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H),5.01 (d, J = 7.6 Hz, 1H), 4.93 (t, 1H), 3.84-3.81 (m, 3H), 3.70 (s,  3carboxamide 2H), 3.38-3.27 (m, 2H), 2.16 (s, 3H), 1.80 (d, J = 12 Hz,2H), 1.49-1.44 (m, 2H), 1.35 (s, 9H) 259

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- ((3,3-difluoro-cyclobutyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.54 (d, J = 8.0 Hz, 1H), 8.38(s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 5.6 Hz, 1H), 7.40 (s,1H), 7.35-7.25 (m, 3H), 4.93-4.88 (m, 1H), 4.17 (d, J = 6.0 Hz, 1H),2.90-2.84 (m, 4H), 2.68-2.55 (m, 20 2H), 2.20 (s, 3H), 1.54 (br s, 2H).260

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (2-((1,3- dihydroxy-propan-2- yl)amino)- 5-methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.39 (d, J = 8.0 Hz, 1H), 8.31(d, J = 15.6 Hz, 2H), 8.10 (s, 1H), 7.42 (s, 1H), 7.31- 7.28 (m, 3H),6.77 (d, J = 8.0 Hz, 1H), 5.02 (s, 2H), 4.56 (s, 2H), 3.89 (br, 1H),3.71 (s, 2H), 3.49-3.47 (m, 4H), 2.18 (s, 3H).  6 261

N-(2-hydroxy- 1-(5-methyl- thiophen-2- yl)ethyl)-1- (5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.24 (s, 1H), 8.14-8.10 (m,2H), 7.36 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 4.0 Hz, 1H), 6.60 (d, J =4.0 Hz, 1H), 5.19-5.07 (m, 2H), 3.89-3.82 (m, 3H), 3.74-3.71 (m, 2H),  3carboxamide 3.38-3.33 (m, 2H), 2.30 (s, 3H), 2.16 (m, 3H), 1.81 (d, J =12.0 Hz, 2H), 1.52-1.43 (m, 2H) 262

N-(3-chloro- 2-(hydroxy- methyl) benzyl)-1-(2- ((4-fluoro- phenyl)-amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR(400 MHz, DMSO-d₆): δ 8.64 (d, J = 6 Hz, 1H), 8.53 (s, 1H), 8.31 (s,1H), 8.16 (s, 1H), 7.70-7.66 (m, 2H), 7.33-7.25 (m, 3H), 7.11 (t, J =8.8 Hz 2H), 5.24 (t, J = 5.2 Hz 1H), 4.76 (d, J = 4.8 Hz, 2H), 4.61 (d,J = 6 Hz, 2H), 2.25 (s, 3H).  3 264

N-((S)-2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2- (((R)-tetra-hydrofuran-3- yl)amino) pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400MHz, DMSO-d₆): δ 8.53 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H),8.09 (s, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.40 (s, 1H), 7.35-7.25 (m, 3H),4.94-4.89 (m, 1H), 4.34 (s, 1H), 3.86- 3.77 (m, 2H), 3.71- 20carboxamide 3.66 (m, 1H), 3.54- 3.51 (m, 1H), 2.97- 2.92 (m, 1H), 2.89-2.85 (m, 1H), 2.18 (s, 3H), 2.16-2.07 (m, 1H), 1.88-1.82 (m, 1H), 1.54(br s, 2H). 265

N-((S)-1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-(((R)-tetra- hydrofuran-3- yl)amino) pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.39 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.28(s, 1H), 8.10 (s, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.31 (s,2H), 7.28 (s, 1H), 5.03-4.99 (m, 2H), 4.41 (s, 1H), 3.86-3.79 (m,  3carboxamide 2H), 3.72-3.68 (m, 3H), 3.54-3.51 (m, 1H), 2.18 (s, 3H),2.11 (s, 1H), 1.89 (s, 1H). 266

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- (benzo[d][1,3]dioxol-5- ylamino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.55 (d, J = 8.4 Hz, 1H), 8.50(s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.41-7.35 (m, 2H), 7.33-7.25 (m,3H), 7.07-7.05 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 5.94 (s, 2H),4.93-4.88 (m, 1H), 2.97-2.85 (m, 2H), 2.25 (s, 3H) 20 267

N-(2-amino- 1-(thiophen- 2-yl)ethyl)- 1-(5-methyl- 2-((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.37 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.24(s, 1H), 8.10 (s, 1H), 7.36-7.33 (m, 2H), 6.99 (s, 1H), 6.96- 6.94 (m,1H), 5.18- 5.16 (m, 1H), 3.84 (s, 1H), 3.82 (m, 2H), 3.38-3.27 (m, 2H),3.02-2.95 (m,  3 2H), 2.17 (s, 3H), 1.82-1.79 (m, 2H), 1.54-1.46 (m,4H). 268

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2- (oxetan-3-ylamino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.53 (d, J = 8 Hz, 1H), 8.36 (s, 1H), 8.27 (s, 1H),8.09-8.08 (b, 2H), 7.40 (s, 1H), 7.35-7.25 (m, 3H), 4.92-4.87 (m, 2H),4.74 (t, J = 6.8 Hz, 2H), 4.50 (t, J = 6 Hz, 2H), 2.97-2.94 20 (m, 1H)2.89-2.84 (m, 1H), 2.19 (s, 3H), 1.54 (bs, 2H). 269

N-(2-amino- 1-(3-chloro- 5-fluoro- phenyl)ethyl)- 1-(2-(benzo [d][1,3]dioxol-5- ylamino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.60 (d, J = 8.0Hz, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.38 (s, 1H), 7.27(d, J = 7.6 Hz, 2H), 7.19 (d, J = 9.6 Hz, 1H), 7.07-7.05 (m, 1H), 6.82(d, J = 8.4 Hz, 1H), 5.94 (s, 2H), 4.91 (d, J = 6.8 Hz, 1H), 2.97-2.85(m, 2H), 2.21 (s,  9 3H). 270

(S)-N-(3- chloro-2- (hydroxy- methyl) benzyl)-1-(5- methyl-2-(tetrahydro- furan-3-yl) amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.63 (t, J = 6.0 Hz, 1H), 8.35(s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.32-7.22(m, 3H), 5.23 (t, J = 4.8 Hz, 1H), 4.76 (d, J = 4.8 Hz, 2H), 4.61 (d, J= 6.0 Hz, 2H), 4.34 (s, 1H), 3.87-3.77 (m, 2H), 3.71-3.66 (m, 1H),3.54-3.51 (m, 1H), 2.19 (s, 3H), 2.18- 2.09 (m, 1H), 1.88- 1.85 (m, 1H). 3 271

N-((S)-2- amino-1-(3- chlorophenyl) ethyl)-1-(2- (chroman-4- ylamino)-5-methyl- pyrimidin-4- yl)-1H- imidazole- 1HNMR (400 MHz, DMSO-d₆): δ 8.53(d, J = 8.0 Hz, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.80 (d,J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.34-7.25 (m, 3H), 7.17-7.16 (m, 1H),7.12-7.09 (m, 1H),  4 4-carboxamide 6.80 (t, J = 7.2 Hz, 1H), 6.74 (d, J= 8.4 Hz, 1H), 5.22 (br s, 1H), 4.93-4.88 (m, 1H), 4.26-4.20 (br s, 2H),2.98-2.94 (m, 1H), 2.93-2.87 (m, 1H), 2.30 (s, 3H), 2.21 (br s, 1H),1.88 (br s, 2H). 272

(S)-N-(2- amino-1-(3- chlorophenyl) ethyl)-1-(5- methyl-2-((3-morpholino- phenyl)amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H), 8.57-8.53 (m, 2H), 8.34 (s,1H), 8.16 (s, 1H), 7.54-7.53 (m, 1H), 7.41 (s, 1H), 7.31- 7.22 (m, 4H),7.03 (t, J = 12 Hz, 1H), 4.92-4.91 (m, 1H), 3.70 (s, 4H), 2.96- 2.88 (m,6H), 2.27  4 (s, 3H), (NH2 peak merged with solvent) 273

N-(3-chloro- 2-(hydroxy- methyl) benzyl)-1-(2- ((3,3-difluoro-cyclobutyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR(400 MHz, DMSO-d₆): δ 8.63 (t, J = 5.6 Hz, 1H), 8.38 (s, 1H), 8.27 (s,1H), 8.12 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 7.32-7.22 (m, 2H),5.25-5.22 (m, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.60 (d, J = 6 Hz, 2H),4.18-  3 carboxamide 4.15 (m, 1H), 2.95- 2.19 (m, 2H), 2.68- 2.60 (m,2H), 2.19 (s, 3H). 274

N-(2-amino- 1-(5-chloro- thiophen-2- yl)ethyl)-1- (5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.45 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.25(s, 1H), 8.11 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 3.6 Hz,1H), 6.84 (d, J = 4.0 Hz, 1H), 5.09-5.05 (m, 1H), 3.85-3.82 (m, 3H),  4carboxamide 3.39-3.27 (m, 2H), 3.026-2.92 (m, 2H), 2.17 (s, 3H), 1.80(d, J = 11.6 Hz, 2H), 1.52-1.44 (m, 2H). 275

(S)-N-(2- amino-1- (3-chloro-5- fluorophenyl) ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino) pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.72 (d, J = 8.0 Hz, 1H), 8.33(s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.27-7.24(m, 2H), 7.17 (d, J = 9.2 Hz, 1H), 7.0 (bs, 1H), 5.15-5.05 (m, 1H),3.95-3.81 (m, 3H), 3.38-3.35 (m, 4H), 2.16 (s, 3H), 20 1.81-1.78 (m,2H), 1.51-1.41 (m, 2H), 1.30 (s, 9H). 276

(R)-N-(2- amino-1-(3- chloro-5- fluoro-phenyl) ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.72 (d, J = 8.0 Hz, 1H), 8.33(s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.27-7.24(m, 2H), 7.17 (d, J = 9.2 Hz, 1H), 7.0 (bs, 1H), 5.15-5.05 (m, 1H),3.95-3.81 (m, 3H), 3.38-3.35 (m, 4H), 2.16 (s, 3H),  4 1.81-1.78 (m,2H), 1.51-1.41 (m, 2H), 1.30 (s, 9H). 277

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((1-methyl-1H- pyrazol-5- yl)amino)- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 9.59 (s, 1H), 8.52 (s. 1H), 8.41-8.39 (d, J = 8.0 Hz, 1H),8.29 (s, 1H), 8.10 (s, 1H), 7.42 (s, 1H), 7.31- 7.28 (m, 4H), 6.21- 6.22(s, 1H), 5.03- 4.98 (m, 2H), 3.72-  6 imidazole-4- 3.70 (m, 2H), 3.6carboxamide (s, 3H), 2.26 (s, 3H). 278

N-(2-amino- 1-(3-chloro- 5-fluoro- phenyl)ethyl)- 1-(2-((3,3- difluoro-cyclobutyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.58 (d, J = 8.0 Hz, 1H), 8.38(s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.27-7.17(m, 3H), 4.91 (d, J = 7.2 Hz, 1H), 4.17 (s, 1H), 2.94-2.85 (m, 5H), 2.20(s, 3H),  4 279

1-(5-methyl- 2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4-yl)-N-((6- methyl- pyridin-2-yl) methyl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.65 (t, J = 5.6 Hz, 1H), 8.34 (s, 1H), 8.27(s, 1H), 8.11 (s, 1H), 7.61 (t, J = 7.2 Hz, 1 H), 7.35 (d, J = 6.8 Hz,1H), 7.10-7.07 (m, 2H), 4.49-4.48 (m, 2H), 3.89 (s, 1H), 3.85-3.82 (m, 3 2H), 3.39-3.26 (m, 2H), 2.44 (s, 3H), 2.18 (s, 3H), 1.82- 1.79 (m,2H), 1.53- 1.43 (m, 2H). 280

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2-((1-methyl-1H- pyrazol-5- yl)amino)- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 9.58 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.51 (s, 1H), 8.28(s, 1H), 8.02 (s, 1H), 7.40 (s, 1H), 7.35-7.25 (m, 4H), 6.21 (s, 1H),4.94-4.88 (m, 1H), 3.65 (s, 3H), 20 imidazole-4- 2.98-2.85 (m, 2H),carboxamide 2.30 (s, 3H), 2.04 (bs, 2 H). 281

1-(5-methyl- 2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-N-(thiazol-2- ylmethyl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.96 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.15(s, 1H), 7.70 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 4.70 (d, J = 6 Hz, 2H), 3.89 (bs, 1H),  3 3.83 (d, J =11.6 Hz, 2H), 3.39-3.27 (m, 2H), 2.18 (s, 3H), 1.81 (d, J = 12.4 Hz,2H), 1.52- 1.43 (m, 2H); 282

N-(2-amino- 1-(3-chloro-5- fluorophenyl) ethyl)-1-(5- methyl-2-(((S)-tetrahydro- furan-3-yl) amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.59 (d, J = 8.4 Hz, 1H), 8.35(s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.60-7.58 (m, 1H), 7.28-7.24 (m,2H), 7.19 (d, J = 9.6 Hz, 1H), 4.94-4.91 (m, 1H), 4.38-4.31 (m, 1H),3.86-3.77 (m, 2H), 3.71-3.66 (m, 1H), 3.54-3.51 (m,  4 1H), 2.99-2.94(m, 1H), 2.91-2.86 (m, 1H), 2.18 (s, 3H), 2.14-2.04 (m, 1H), 1.88-1.85(m, 1H). 283

N-(2-(amino- methyl) benzyl)-1- (5-methyl-2- ((tetrahydro- 2H-pyran-4-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.78 (t, J = 6.0 Hz, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 8.08(s, 1H), 7.35-7.31 (m, 2H), 7.28-7.26 (m, 1H), 7.20-7.15 (m, 2H), 4.49(d, J = 6.0 Hz, 2H), 3.84-3.82 (m, 4H), 3.36 (t, J =  3 10.0 Hz, 2H),2.16 (s, 3H), 1.80 (d, J = 11.2 Hz, 2H), 1.52- 1.43 (m, 2H). 284

N-((3-(hydroxy- methyl) thiophen-2- yl)methyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.59 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H),8.10 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 6.93(d, J = 5.2 Hz, 1H), 5.02 (t, J = 5.2 Hz, 1H), 4.57-4.56 (m, 2H),4.51-4.49  3 carboxamide (m, 2H), 3.88 (br s, 1H), 3.88-3.81 (m, 3H),3.39-3.27 (m, 2H), 2.16 (s, 3H), 1.80 (d, J = 11.2 Hz, 2H), 1.51-1.43(m, 2H). 285

N-(2-(amino- methyl)-3- chlorobenzyl)- 1-(5-methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H),8.09 (s, 1H), 7.35-7.22 (m, 3H), 7.20 (d, J = 7.6 Hz, 1H), 4.56 (d, J =6.0 Hz, 2H), 3.91-3.84 (m, 4H), 3.88-3.26 (m, 2H), 2.16 (s, 3H),  4 1.97(d, J = 7.6 Hz, 1H), 1.80 (d, J = 11.2 Hz, 2H), 1.48 (t, J = 11.2 Hz,2H). 286

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- ((4,4-difluoro-cyclo-hexyl) amino)-5- methyl- pyrmidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.63 (d, J = 8.4 Hz, 1H), 8.35(s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.43-7.27 (m, 5H), 5.02-5.0 (m,1H), 3.9 (bs, 1H), 3.09- 3.04 (m, 1H), 2.98- 2.93 (m, 1H), 2.17 (s, 3H),2.04-1.97 (m, 2H), 1.91-1.88 (m, 4H), 1.58-1.55 20 (m, 2H). 287

N-(2-(hydroxy- methyl)benzyl)- 1-(5-methyl-2- ((tetrahydro- 2H-pyran-4-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.48 (t, J = 6.0 Hz, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 8.09(s, 1H), 7.35-7.33 (m, 1H), 7.28-7.26 (m, 1H), 7.21-7.19 (m, 1H),5.21-5.18 (m, 1H), 4.59 (d, J = 5.2 Hz, 2H), 4.47 (d, J =  3 6.0 Hz,2H), 3.94- 3.88 (m, 1H), 3.84- 3.81 (m, 2H), 3.39- 3.33 (m, 2H), 2.16(s, 3H), 1.83-1.79 (m, 2H), 1.51-1.43 (m, 2H). 288

(S)-N-(2- amino-1-(3- chloro-5- fluoro-phenyl) ethyl)-1-(2-((3,3-difluoro- cyclobutyl) amino)-5- methyl- pyrimidin-4- yl)-1H-imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.60 (d, J = 8.4 Hz1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.87 (d, J = 8.4 Hz 1H),7.24 (m, 3H), 4.93 (d, J = 8 Hz 1H), 4.16 (s, 1H), 2.93 (m, 5H), 2.2 (s,3H), 1.96 (s, 2H).  4 289

(R)-N-(2- amino-1-(3- chloro-5- fluoro-phenyl) ethyl)-1-(2-((3,3-difluoro- cyclobutyl) amino)-5- methyl- pyrimidin-4- yl)-1H-imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.60 (d, J = 8.4Hz, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.87 (d J = 8.4 Hz,1H), 7.25 (m, 3H), 4.93 (d, J = 8 Hz, 1H), 4.16 (s, 1H), 2.95-2.9 (m,5H), 2.2 (s, 3H).  4 290

N-(2-amino- 1-(5-chloro- thiophen-2- yl)ethyl)-1- (5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide (enantiomer #1) 1HNMR (400 MHz, DMSO-d₆): δ 8.58 (d, J = 8.4Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.35 (d, J = 7.2 Hz,1H), 6.95 (d, J = 3.6 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 5.18 (d, J =6.4 Hz, 1H), 3.85-3.82 (m, 3H), 3.38-3.27 (m, 2H), 3.13-3.06 (m, 2H),2.16 (s, 3H),  4 1.80 (d, J = 11.6 Hz, 2H), 1.52-1.44 (m, 2H). 291

N-(2-amino- 1-(5-chloro- thiophen-2- yl)ethyl)-1- (5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide (enantiomer #2) 1HNMR (400 MHz, DMSO-d₆): δ 8.49 (d, J = 8.4Hz, 1H), 8.34 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.35 (d, J = 7.2 Hz,1H), 6.95 (d, J = 3.6 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 5.18 (d, J =6.4 Hz, 1H), 3.85-3.82 (m, 3H), 3.38-3.27 (m, 2H), 3.13-3.06 (m, 2H),2.16 (s, 3H),  4 1.80 (d, J = 11.6 Hz, 2H), 1.52-1.44 (m, 2H). 292

N-((S)-2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- (cyclohex-3-en-1-ylamino)- 5-methyl- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.53 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.26(s, 1H), 8.07 (s, 1H), 7.04 (s, 1H), 7.34- 7.26 (m, 4H), 5.62 (bs, 2H),4.91-4.89 (m, 1H), 3.9 (bs, 1H), 2.94-2.92 (m, 1H), 2.89-2.87 (m, 201H), 2.28 (s, 1H), 2.17 (s, 3H), 2.09 (bs, 2H), 1.89-1.87 (m, 5H). 293

N-(2-(2- hydroxy- propan-2- yl)benzyl)-1- (5-methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.37 (s, 1H), 8.34 (d, J = 10.4 Hz, 1H), 8.22 (s, 1H), 8.06(s, 1H), 7.35-7.29 (m, 3H), 7.15 (t, J = 3.6 Hz, 2H), 4.76 (d, J = 6.4Hz, 2H), 3.91 (bs, 1H), 3.8 (d, 11.2 Hz, 2H), 3.37  3 carboxamide (d, J= 11.2 Hz, 2H), 2.16 (s, 3H), 1.80 (d, J = 12 Hz, 2H), 1.55 (s, 6H),1.47 (d, J = 12.0 Hz, 2H) 294

N-((3-(amino- methyl) thiophen-2- yl)methyl)-1- (5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.71 (t, J = 6.0 Hz, 1H), 8.33 (s, 1H), 8.23(s, 1H), 8.09 (s, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 4.8 Hz,1H), 6.97 (d, J = 4.8 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.90 (br s,  4carboxamide 1H), 3.84-3.81 (m, 2H), 3.72 (s, 2H), 3.36 (t, J = 11.2 Hz,2H), 2.16 (s, 3H), 1.81 (d, J = 12.0 Hz, 2H), 1.48 (d, J = 8.8 Hz, 2H).295

(S)-N-(1- (3-chloro-5- fluorophenyl)- 2-hydroxy- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.43 (d, J = 8.0 Hz, 1H), 8.33(s, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.35 (d, J = 6.8 Hz, 1H), 7.29-7.25(m, 2H), 7.20 (d, J = 9.6 Hz, 1H), 5.07-5.0 (m, 2H), 3.88-3.82 (m, 3H),3.71 (t, J = 8.0, 2H), 3.36 (t, J = 10.8 Hz, 2H),  3 2.17 (3H), 1.80 (d,J = 11.6 Hz, 2H), 1.48 (d, J = 8.8 Hz, 2H). 296

(S)-N-(1-(3- chlorophenyl)- 2-hydroxy- ethyl)-1- (5-methyl-2-((1-methyl- piperidin-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.45 (d, J = 8.0 Hz, 1H), 8.32(s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.42 (s, 1H), 7.31 (m, 4H), 5.03(m, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.63 (s, 1H), 2.73 (d, J = 10.0 Hz,2H), 2.16- 2.14 (m, 5H), 1.95 (s, 2H), 1.81 (d,  6 J = 11.2 Hz, 2H),1.52-1.44 (m, 2H) 297

N-(3-chloro- 5-fluoro-2- (hydroxy- methyl)- benzyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.73 (t, 1H), 8.33 (s, 1H), 8.26(s, 1H), 8.11 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.30- 7.28 (m, 1H),7.10- 7.07 (m, 1H), 5.22 (t, J = 5.6 Hz, 1H), 4.71 (d, J = 5.2 Hz, 2H),4.60 (d, J = 6 Hz, 2H), 3.89 (s, 1H), 3.83 (d, J =  3 10.8 Hz, 2H),3.39- 3.32 (m, 2H), 2.17 (s, 3H), 1.82 (t, 2H), 1.53-1.44 (m, 2H). 298

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.90 (d, J = 9.2 Hz, 1H), 8.35 (s, 1H), 8.29(s, 1H), 8.14 (s, 1H), 7.97 (br s, 3H), 7.51 (s, 1H), 7.42-7.37 (m, 4H),5.32 (d, J = 4.4 Hz, 1H), 3.83 (d, J = 11.6 Hz, 3H), 3.38-3.35 20carboxamide (m, 2H), 3.31-3.23 hydrochloride (m, 2H), 2.16 (s, salt 3H),1.80 (d, J = 12.8 Hz, 2H), 1.52- 1.42 (m, 2H). 299

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide p-toluene- sulfonic acid salt 1HNMR (400 MHz, DMSO-d₆): δ8.81 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H),7.49-7.44 (m, 2H), 7.41-7.35 (m, 4H), 7.09-7.07 (br s, 3H), 5.24 (d, J =4 Hz, 1H), 3.85-3.82 (m, 3H), 3.38-3.27 (m, 3H), 3.18-3.13 (m, 1H), 2.30(s, 3H), 2.16 (s, 2H), 1.80 (d, J = 11.6 Hz, 2H), 1.52-1.44 (m, 2H). 20300

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide benzenesulfonic acid salt 1HNMR (400 MHz, DMSO-d₆): δ 8.89(d, J = 9.2 Hz, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.91 (brs, 3H), 7.58 (d, J = 5.6 Hz, 2H), 7.51 (s, 1H), 7.42- 7.35 (m, 4H), 7.28(d, J = 6 Hz, 3H), 5.34-5.31 (m, 1H), 3.85-3.82 (m, 3H), 3.41-3.32 (m,3H), 3.28 (s, 1H), 2.16 (s, 3H), 1.80 (d, J = 11.6 Hz, 2H), 1.52-1.54(m, 2H). 20 301

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- ((3,3-difluoro-cyclobutyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR(400 MHz, DMSO-d₆): δ 8.90 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H), 8.31 (s,1H), 8.18 (s, 1H), 7.88 (d, J = 4.8 Hz, 1H), 7.62 (br s, 3H), 7.50 (s,1H), 7.38- 7.35 (m, 3H), 5.29 (d, J = 4 Hz, 1H), 4.16 (s, 1H), 3.39- 20carboxamide 3.28 (m, 1H), 3.18- hydrochloride salt 3.14 (m, 1H), 2.92(t, 2H), 2.61 (t, 2H), 2.19 (s, 3H) 302

(S)-N-(2- amino-2-(3- chloro-5- fluoro-phenyl) ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide benzenesulfonic acid salt 1HNMR (400 MHz, DMSO-d₆): δ 8.92(d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.83 (brs, 3H), 7.57 (d, J = 6.4 Hz, 2H), 7.37 (s, 3H), 7.28 (d, J = 6.4 Hz,4H), 5.32 (d, J = 4.4 Hz, 1H), 3.83 (d, J = 11.6 Hz, 3H), 3.41- 3.27 (m,3H), 3.18- 3.14 (m, 1H), 2.16 (s, 3H), 1.80 (d, J = 12 Hz, 2H),1.52-1.44 (m, 2H). 20 303

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- ((3,3-difluoro-cyclo-butyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide p-toluene- sulfonic acid salt 1HNMR (400 MHz, DMSO-d₆): δ8.88 (d, J = 9.2 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.87(d, J = 5.2 Hz, 2H), 7.75 (br s, 3H), 7.51 (s, 1H), 7.46- 7.42 (m, 2H),7.40- 7.35 (m, 3H), 7.08 (d, J = 7.6 Hz, 2H), 5.31 (d, J = 4.4 Hz, 1H),4.16 (s, 1H), 3.40-3.27 (m, 1H), 3.24-3.19 (m, 1H), 2.94-2.91 (m, 2H),2.64-2.61 (t, 2H), 2.26 (s, 3H), 2.19 (s, 3H). 20 304

(S)-N-(2- amino-1-(3- chlorophenyl)- ethyl)-1-(2- ((3,3-difluoro-cyclobutyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide benzene- sulfonic acid salt 1HNMR (400 MHz, DMSO-d₆): δ 8.88(d, J = 8.8 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.87 (d,J = 4.8 Hz, 1H), 7.72 (br s, 3H), 7.57 (d, J = 6 Hz, 2H), 7.51 (s, 1H),7.42-7.37 (m, 3H), 7.28 (d, J = 6.4 Hz, 3H), 5.31 (d, J = 4.4 Hz, 1H),4.16 (s, 1H), 3.39-3.27 (m, 1H), 3.23 (d, J = 4.8 Hz, 1H), 2.94- 2.91(m, 2H), 2.63 (d, J = 12 Hz, 2H), 2.19 (s, 3H) 20 305

(S)-N-(2- amino-1-(3- chloro-5- fluoro-phenyl) ethyl)-1-(5- methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.95 (d, J = 8.8 Hz, 1H), 8.35(s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 8.00 (br s, 3H), 7.37 (br s, 3H),7.28 (d, J = 9.6 Hz, 1H), 5.34-5.31 (m, 1H), 3.85-3.82 (m, 3H),3.37-3.33 (m, 3H), 3.26-3.23 (m, 1H), 2.16 (s, 3H), 1.80 20hydrochloride (d, J = 11.6 Hz, 2H), salt 1.52-1.44 (m, 2H) 306

(S)-N-(2- (((1H-pyrrol- 2-yl)-methyl) amino)-1-(3- chlorophenyl)-ethyl)-1-(5- methyl-2- ((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4-yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 10.50 (s,1H), 8.50 (d, J = 8.0 Hz, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H),7.41 (s, 1H), 7.36-7.25 (m, 4H), 6.58 (s, 1H), 5.86 (s, 1H), 5.82 (s,1H), 5.06 (d, J = 5.6 Hz, 1H), 3.85-3.82 (m, 3H), 3.65 (s, 2H), 3.36 (t,J = 11.2 Hz, 2H), 2.95-2.90 (m, 20 1H), 2.82-2.79 (m, 1H), 2.17 (s, 3H),1.81 (d, J = 11.6 Hz, 2H), 1.52-1.47 (m, 2H). 307

N-((6-chloro- pyridin-2- yl)methyl)- 1-(5-methyl- 2-((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.75 (bs, 1H), 8.34 (s, 1H), 8.28 (s, 1H),8.12 (s, 1H), 80 (t, J = 7.6 Hz, 1H), 7.37-7.35 (m, 2H), 7.29 (d, J =7.6 Hz, 1H), 4.50 (d, J = 6.4 Hz, 2H), 3.89 (b, 1H), 3.84  3 (d, J =10.8 Hz, 2H), 3.37 (t, J = 10.8 Hz, 2H), 2.18 (s, 3H), 1.81 (d, J = 11.6Hz, 2H), 1.50-1.47 (m, 2H). 308

(S)-N-(1-(3- chlorophenyl)- 2-((tetrahydro- 2H-pyran-4- yl)amino)-ethyl)-1-(5- methyl-2- ((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4-yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆): δ 8.49 (d, J= 6.8 Hz, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.43 (s, 1H),7.32- 7.27 (m, 4H), 5.01 (bs, 1H), 3.85-3.76 (m, 4H), 3.36 (t, J = 11.6Hz, 2H) 3.27 (s, 2H), 2.98 (bs, 1H), 2.90 (bs, 1H), 2.48 (s, 1H), 2.17(s, 3H), 1.85 20 (bs, 25.6 Hz, 2H), 1.74 (t, J = 18.8 Hz, 2H), 1.52-1.47(m, 2H), 1.27 (bs, 3H). 309

N-(3-chloro- 2-fluoro- benzyl)-1-(5- methyl-2- ((tetrahydro- 2H-pyran-4-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.72 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.11(s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.36-7.28 (m, 2H), 7.17 (t, J = 8 Hz,1H), 4.50 (d, J = 6.0 Hz, 2H), 3.92-3.82 (m, 3H),  3 3.36 (t, J = 11.2Hz, 2H), 2.17 (s, 3H), 1.81 (d, J = 12.0 Hz, 2H), 1.56-1.43 (m, 2H). 310

(S)-N-(3- cyano-benzyl)- 1-(5-methyl-2- ((tetrahydro- furan-3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.82 (bs, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 8.12 (s, 1H),7.71- 7.68 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.60 (bs, 1H), 7.54- 7.50(m, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.35 (bs, 1H), 3.87-  3 3.81 (m, 2H),3.72- 3.70 (d, J = 8.0 Hz, 1H), 3.54-3.53 (m, 1H), 2.19 (s, 3H),2.15-2.10 (m, 1H), 1.87-1.85 (m, 1H). 311

(S)-1-(5- methyl-2- ((tetrahydro- furan-3- yl)amino)- pyrimidin-4-yl)-N-(3- (trifluoro- methyl) benzyl)-1H- imidazole-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.84 (t, J = 6.4 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 8.12(s, 1H), 7.65 (s, 1H), 7.62- 7.52 (m, 4H), 4.50 (d, J = 6.4 Hz, 2H),4.36 (bs, 1H), 3.87- 3.80 (m, 2H), 3.70- 3.68 (m, 1H), 3.55-  3carboxamide 3.27 (m, 1H), 2.19 (s, 3H), 2.13-2.12 (m, 1H), 1.86 (bs,1H). 312

N-(2-amino- 1-(3-chloro- phenyl)-2- oxoethyl)-1- (5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1HNMR (400 MHz, DMSO-d₆): δ 8.34- 8.28 (m, 3H), 8.12 (s, 1H), 7.86 (s,1H), 7.48 (s, 1H), 7.42- 7.36 (m, 5H), 5.51 (d, J = 7.6 Hz, 1H), 3.88(s, 1H), 3.84 (d, J = 11.6 Hz, 2H), 3.36 (t, J = 11.8 Hz, 2H), 2.16  3carboxamide (s, 3H), 1.81 (d, J = 11.6 Hz, 2H), 1.52-1.44 (m, 2H), 313

(S)-N-(3,5- dichloro benzyl)-1- (5-methyl-2- ((tetrahydro- furan-3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz,DMSO-d₆): δ 8.80 (bs, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 8.12 (s, 1H),7.57- 7.53 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 4.40 (d, J = 6.4 Hz, 2H),4.36 (bs, 1H), 3.87-3.78 (m, 2H), 3.72-3.68 (m, 1H), 3.55-3.52 (m, 1H),2.19 (s, 3H), 2.15-  3 2.10 (m, 1H), 1.87- 1.85 (m, 1H). 314

(S)-N-(3,4- dichloro- benzyl)-1- (5-methyl-2- ((tetrahydro- furan-3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1H NMR (400MHz, DMSO-d₆): δ 8.81 (t, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H),8.12 (s, 1H), 7.58-7.53 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 4.41-4.36 (m,3H), 3.87-3.78 (m, 2H), 3.72-3.66 (m, 1H), 3.55-3.52 (m, 1H), 2.19 (s,3H),  3 2.15-2.08 (m, 1H), 1.88-1.85 (m, 1H). 315

(S)-N-(3- chloro-2- fluorobenzyl)- 1-(5-methyl- 2-((tetrahydro- furan-3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1H NMR (400MHz, DMSO-d₆): δ 8.73 (t, J = 6 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H),8.13 (s, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.46-7.28 (m, 1H), 7.32-7.28 (m,1H), 7.17 (t, J = 8 Hz, 1H), 4.50 (d, J = 4 Hz, 2H), 4.35  3 (bs, 1H),3.87-3.78 (m, 2H), 3.72-3.68 (m, 1H), 3.55-3.52 (m, 1H), 2.19 (s, 3H),2.15-2.08 (m, 1H), 1.89-1.6 (m, 1H). 316

(S)-N-(2,6- difluoro- benzyl)-1- (5-methyl- 2-((tetrahydro- furan-3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1H NMR (400MHz, DMSO-d₆): δ 8.38 (bs, 2H), 8.27 (s, 1H), 8.13 (s, 1H), 7.63 (bs,1H), 7.38 (m, 1H), 7.08 (m, 2H), 4.55 (d, J = 5.6 Hz, 2H), 4.38 (bs,1H), 3.88-3.83 (m, 2H), 3.73-3.71 (m, 1H), 3.57 (bs,  3 1H), 2.21 (s,3H), 2.16-2.13 (m, 1H), 1.90 (bs, 1H). 317

(S)-N-(2- chloro-3- (trifluoro- methyl) benzyl)-1- (5-methyl-2-((tetrahydro- furan-3- yl)amino)- pyrimidin-4- 1H NMR (400 MHz,DMSO-d₆): δ 8.82 (bs, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H),7.76 (d, J = 7.6 Hz 1H), 7.61 (d, J = 6.4 Hz, 2H), 7.54-7.51 (m, 1H),4.57 (d, J = 6.0 Hz, 2H), 4.36  3 yl)-1H- (bs, 1H), 3.88-3.79imidazole-4- (m, 2H), 3.73-3.69 carboxamide (m, 1H), 3.56-3.54 (m, 1H),2.21 (s, 3H), 2.16-2.11 (m, 1H), 1.90-1.87 (m, 1H). 318

(S)-N-(3- chloro-benzyl)- 1-(5-methyl-2- ((tetrahydro- furan-3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1H NMR (400 MHz,DMSO-d₆): δ 8.77 (t, J = 6.0 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 8.12(s, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.34-7.25 (m, 4H), 4.42 (d, J = 6.4Hz, 2H), 4.35 (bs, 1H), 3.88-3.78 (m, 2H), 3.72-3.66 (m,  3 1H),3.55-3.52 (m, 1H), 2.20 (s, 3H), 2.17-2.08 (m, 1H), 1.90-1.83 (m, 1H).319

(S)-N-(2,3- dichloro- benzyl)-1- (5-methyl-2- ((tetrahydro- furan-3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1H NMR (400 MHz,DMSO-d₆): δ 8.82 (bs, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.21 (s, 1H),7.67 (bs, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.33(d, J = 7.2 Hz, 1H), 4.58 (d, J = 6.4 Hz, 2H), 4.42 (bs,  3 1H),3.94-3.84 (m, 2H), 3.78-3.73 (m, 1H), 3.61-3.33 (m, 1H), 2.26 (s, 3H),2.21-2.15 (m, 1H), 1.93-1.92 (m, 1H). 320

(S)-N-(1-(3- chlorophenyl)- 2-(dimethyl- amino)-ethyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1H NMR (400 MHz, DMSO-d₆): δ 8.41- 8.39 (d, J = 8 Hz, 1H), 8.3 (s, 1H),8.26 (s, 1H), 7.47 (s, 1H), 7.36-7.30 (q, J = 6 Hz, 3H), 7.26 (d, J = 4Hz, 1H), 5.04 (t, J = 6 Hz, 1H), 3.89 (bs, 1H), 3.85 (d, J = 16 20carboxamide Hz, 2H), 3.36 (t, J = 12 Hz, 2H), 2.78 (t, J = 12 Hz, 1H),2.42 (s, 1H), 2.18 (s, 10 H), 1.80 (d, J = 12 Hz, 2H), 1.52-1.44 (m,2H). 321

(S)-N-(3- fluoro-4- (trifluoro- methyl)benzyl)- 1-(5-methyl-2-((tetrahydro- furan-3-yl) amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1H NMR (400 MHz, DMSO-d₆): δ 8.89- 8.86 (m, 1H), 8.36 (s,1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.60 (bs, J =8.0 Hz, 1H), 7.39-7.32 (m, 2H), 4.50 (d, J = 4 Hz, 2H), 4.36 (s, 1H)3.88-3.78 (m, 2H), 3.72-3.67 (m, 1H), 3.55-3.52 (q, 1H), 2.20 (s, 1H), 3 2.15-2.08 (m, 1H), 1.86 (t, 1H), 1.22 (s, 1H). 322

(S)-N-(2- chloro-6- (trifluoro- methyl)- benzyl)-1- (5-methyl-2-((tetra- hydrofuran- 3-yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- 1HNMR (400 MHz, DMSO-d₆): δ 8.35 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.88(s, 1H), 7.84 (d, J = 8 Hz, 1H), 7.77-7.75 (d, J = 8 Hz, 1H), 7.60-7.56(m, 2H), 4.70 (d, J = 4 Hz, 2H), 4.36 (s, 1H), 3.87-3.78 (m, 2H),3.71-3.66 (m, 1H),  3 carboxamide 3.54-3.52 (m, 1H), 2.15 (s, 3H), 2.13-2.08 (m, 1H), 1.88- 1.85 (m, 1H). 323

(S)-1-(5- methyl-2- ((tetrahydro- furan-3-yl) amino)- pyrimidin-4-yl)-N- (3-methyl- benzyl)-1H- imidazole-4- carboxamide 1H NMR (400 MHz,DMSO-d₆): δ 8.59 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.59(d, J = 8 Hz, 1H), 7.17 (t, J = 12 Hz, 1H), 7.11- 7.09 (m, 2H), 7.02 (d,J = 7.6 Hz, 1H), 4.39 (d, J = 8 Hz, 3H), 3.88-3.78 (m,  3 2H) 3.72-3.69(m, 1H), 3.55-3.52 (m, 1H), 2.26 (s, 3H), 2.20 (s, 3H), 2.15- 2.08 (m,1H) 1.89- 1.76 (m, 1H). 324

(S)-N-(4- chloro-3- fluorobenzyl)- 1-(5-methyl- 2-((tetrahydro-furan-3-yl) amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1H NMR(400 MHz, DMSO-d₆): δ 8.79 (t, J = 6.0 Hz, 1H), 8.36 (s, 1H), 8.28 (s,1H), 8.12 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H),7.30 (d, J = 5.4 Hz, 1H), 7.16 (d, J = 4.2 Hz, 1H), 4.42 (d, J = 3.4 Hz,2H), 4.36 (s, 1H), 3.88-  3 3.78 (m, 2H), 3.72- 3.66 (m, 1H), 3.55- 3.52(m, 1H), 2.19 (s, 3H), 2.15-2.09 (m, 1H), 1.89-1.86 (m, 1H) 325

N-(2-(hydroxy- methyl)-3- methylbenzyl)- 1-(5-methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆) δ 8.47- 8.44 (m, 1H), 8.33 (s, 1H), 8.23 (s, 1H),8.08 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.15 (d, 1H), 7.11 (t, J = 7.6Hz, 1H), 7.05 (d, J = 6.4 Hz, 1H), 4.99 (t, J = 5.6 Hz, 1H), 4.60 (d,  3J = 5.2 Hz, 2H), 4.56 (m, 2H), 3.85 (m, J = 14.8 Hz, 3H), 3.36 (t, J =10.8 Hz, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 2.05 (s, 1H), 1.81 (d, J =11.6 Hz, 2H), 1.53-1.44 (m, 2H), 1.22 (s, 1H). 326

(S)-N-(1-(3- chlorophenyl)- 2-(methyl- amino)ethyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-1H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 8.27(s, 1H), 8.07 (s, 1H), 7.43 (s, 1H), 7.36- 7.27 (m, H), 5.11- 5.06 (m,1H), 3.85- 3.82 (m, 3H), 3.39- 3.27 (m, 2H), 3.00- 2.95 (m, 1H), 2.85-20 carboxamide 2.80 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 1.81 (d, J =11.2 Hz, 2H), 1.53-1.43 (q, 2H), 1.22 (s, 1H). 327

(S)-1-(5- methyl-2- ((tetrahydro- furan-3- yl)amino) pyrimidin-4-yl)-N-(3-tert- butylbenzyl)- 1H-imidazole- 4-carboxamide 1H NMR (400MHz, DMSO-d₆) δ 8.607 (t, J = 6.0 Hz, 1H), 8.35 (s 1H), 8.27 (s 1H), δ8.12 (s 1H), 7.59 (d, J = 2.6 Hz, 1H), 7.35 (s 1H), 7.25-7.19 (m, 2H),7.10 (d, J = 3.2 Hz, 1H), 4.42 (d, J = 3.2 Hz, 2H), 3.86-3.80  3 (m,2H), δ (m, 1H), δ (m, 1H), 2.197 (s, 3H), δ (q, 1H), δ (q, 1H), 1.25 (s,9H), 328

N-((2-chloro- 5-methyl- thiazol-4- yl)methyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1H NMR (400 MHz, DMSO-d₆) δ 8.43 (t, J = 5.2 Hz, 1H), 8.33(s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 4.38 (d,J = 6.0 Hz, 2H), 3.89-3.82 (m, 3H), 3.36 (t, J = 11.6 Hz, 2H), 2.42 (s,3H), 2.16 (s, 3H), 1.81 (d, J = 12.0 Hz, 2H), 1.52-1.44 (m,  3 2H). 329

N-(3-chloro- 2-(hydroxy- methyl)- benzyl)-1-(2- ((2-chloro-4-fluoro-phenyl) amino)-5- methyl- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1H NMR (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.63 (t, J = 6 Hz,1H), 8.46 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.67- 7.63 (m, 1H), 7.50-7.47 (dd, J = 8.8 Hz, 1H), 7.32-7.20 (m, 4H), 5.24 (t, J = 4.8 Hz, 1H),4.75 (d, J = 4.8 Hz, 2H), 4.6  3 (d, J = 6, 2H), 2.25 (s, 3H). 330

N-(4-chloro- 3-(hydroxy- methyl)- benzyl)-1-(5- methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆) δ 8.70 (t, J = 6 Hz, 1H), 8.34 (s, 1H), 8.25(s, 1H), 8.09 (s, 1H), 7.51 (s, 1H), 7.36-7.30 (m, 2H), 7.19 (d, J = 8Hz, 1H), 5.34 (t, J = 4 Hz, 1H), 4.51 (d, J = 4 Hz, 2H), 4.21 (d, J = 4Hz, 2H), 3.90 (bs, 1H), 3.84 (d, J = 12 Hz, 2H), 3.39- 303 (m, 2H), 2.17 3 (s, 3H), 1.84-1.79 (m, 2H), 1.52- 1044 (m, 2H). 331

(S)-N-(3- chloro-2- methylbenzyl)- 1-(5-methyl-2- ((tetrahydro- furan-3-yl)amino) pyrimidin-4- yl)-1H- imidazole-4- carboxamide 1H NMR (400 MHz,DMSO-d₆) δ 8.60 (t, J = 6.4 Hz, 1H), 8.36 (s 1H), 8.28 (s 1H), 8.13 (s1H), 7.60-7.58 (d, J = 4 Hz, 1H), 7.31-7.29 (d, J = 4 Hz 1H), 7.21 (d, J= 4 Hz, 1H), 7.136 (t, J = 15.2 Hz, 1H), 4.45  3 (d, J = 2 Hz, 2H), 4.36(d, J = 2 Hz, 1H), 3.88-3.78 (m, J = 19.2 Hz, 2H), 3.72-3.68 (m, 1H),3.55-3.52 (m, 1H), 2.30 (s, J = 1.4 Hz, 3H), 2.17 (s, 3H), 2.13-2.08 (m,1H), 1.90-1.83 (m, 1H). 332

N-(3-chloro- 2-(hydroxy- methyl)- benzyl)-1-(2- ((2,2-difluoro-benzo[d][1,3] dioxol-5-yl) amino)-5- methyl- pyrimidin-4- yl)-1H-imidazole-4- carboxamide 1H NMR (400 MHz, DMSO-d₆) δ 8.68- 8.65 (t, J =6.4 Hz, 1H), 8.57 (s, 1H), 8.34 (d, J = 0.8 Hz, 1H), 8.19 (s, 1H), 7.88(d, J = 8 Hz, 1H), 7.38-7.23 (m, 5H), 5.25 (t, J = 5.2 Hz, 1H), 4.76 (d,J = 5.2 Hz, 2H), 4.62 (d, J = 6.4 Hz, 2H), 2.30 (s, 3H), 1.21 (s, 1H). 3 333

(S)-N-(1-(3- chlorophenyl)- 2-((2-hydroxy- ethyl)amino) ethyl)-1-(5-methyl-2- ((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H-imidazole-4- carboxamide 1HNMR (400 MHz, DMSO-d₆) δ 8.50 (d, J = 8.0 Hz,1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.43 (s, 1H), 7.36- 7.27(m, 4H), 5.07- 5.04 (m, 1H), 4.41 (t, J = 5.6 Hz, 1H), 3.85-3.82 (m,3H), 3.42-3.27 (m, 4H), 3.07.2.99 (m, 1H), 2.92-2.86 (m, 1H), 20 2.57(br s, 2H), 2.17 (s, 3H), 1.81 (d, J = 11.2 Hz, 2H), 1.66 (br s, 1H),1.52- 1.44 (m, 2H). 334

N-(3-chloro- 2-hydroxy- ethylbenzyl)- 1-(5-methyl- 2-((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆) 8.64-8.63 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H),8.25 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.20(d, J = 8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 3 4.83 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 6 Hz, 2H), 3.85-3.82 (m, 2H),3.58 (q, 2H), 3.39-3.34 (m, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.17 (s, 3H),1.81 (d, J = 10.8 Hz, 2H), 1.53-1.43 (m, 2H), 1.21 (s, 1H). 335

N-(2-chloro- 3-(hydroxy- methyl)- benzyl)-1-(5- methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆) δ 8.63- 8.61 (t, J = 6 Hz, 1H), 8.34 (s, 1H),8.28 (s, 1H), 8.12 (s, 1H), 7.43 (d, J = 6.8 Hz, 1H), 7.35 (d, J = 6.8Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.20-7.19 (d, J = 7.6 Hz, 1H), 5.34(t, J = 5.6 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.51 (d, J = 5.6 Hz, 2H), 3 3.90 (br s, 1H), 3.85-3.82 (d, J = 11.6 Hz, 2H), 3.37 (t, J = 10.8Hz, 2H), 2.18 (s, 3H), 1.81 (d, J = 11.6 Hz, 1H), 1.52-1.45 (m, 2H). 336

(R)-N-(3- chloro-2- (hydroxy- methyl)- benzyl)-1-(2- ((1-hydroxy-butan-2-yl) amino)-5- methyl- pyrimidin-4- 1HNMR (400 MHz, DMSO-d₆) δ8.63- 8.61 (m, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.33- 7.23(m, 3H), 6.97- 6.95 (d, J = 8 Hz, 1H), 5.24 (t, J = 5.2 Hz, 1H), 4.76(d, J = 5.6 Hz, 2H),  3 yl)-1H- 4.61-4.54 (m, 3H), imidazole-4- 3.81 (brs, 1H), carboxamide 3.45-3.41 (m, 1H), 3.36-3.27 (m, 1H), 2.17 (s, 3H),1.66- 1.61 (m, 1H), 1.44- 1.37 (m, 1H), 0.85 (t, J = 6.8 Hz, 3H). 337

(S)-N-(1-(3- chlorophenyl)- 2-(neopentyl- amino)-ethyl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆) δ 8.52 (d, J = 11.2 Hz, 1H), 8.33(s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.43 (s, 1H), 7.35-7.26 (m, 4H),5.05 (q, 1H), 3.89- 3.82 (m, 3H), 3.36 (t, J = 10.8 Hz, 2H), 2.99-2.83(m, 2H), 2.30-2.24 (m, 2H), 2.17 (s, 3H), 1.80 20 (d, J = 11.2 Hz, 2H),1.53-1.43 (m, 3H), 0.80 (s, 9H). 338

(S)-N-(2- chloro-3- (hydroxy- methyl)- benzyl)-1-(5- methyl-2-((tetrahydro- furan-3- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4-carboxamide 1HNMR (400 MHz, DMSO-d₆) δ 8.64- 8.62 (t, J = 5.6 Hz, 1H),8.36 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.43(d, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H),5.34 (t, J = 5.2 Hz, 1H), 4.58-4.50 (m, 4H), 4.35 (br s, 1H), 3.88-3.80(m, 2H),  3 3.69 (q, 1H), 3.55- 3.27 (m, 1H), 2.20 (s, 3H), 2.14-2.12(m, 1H), 1.89-1.86 (m, 1H). 339

1-[5-Methyl- 2-(tetrahydro- pyran-4- ylamino)- pyrimidin-4- yl]-1H-imidazole-4- carboxylic acid [(S)-1- (3-chloro- phenyl)-2- (cyclopropyl-methyl-amino)- 1HNMR (400 MHz, DMSO-d₆) δ 8.48 (d, J = 7.6 Hz, 1H), 8.34(s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.42 (s, 1H), 7.36-7.27 (m, 4H),5.05-5.02 (m, 1H), 3.85-3.82 (m, 3H), 3.36 (t, J = 11.6 Hz, 2H),3.01-2.86 (m, 2H), 2.38-2.37 (m, 2H), 2.17 (s, 3H), 20 ethyl]-amide 1.80(d, J = 11.6 Hz, 2H), 1.52-1.44 (m, 2H), 1.21 (br s, 1H), 0.93-0.83 (m,1H), 0.35 (d, J = 8.0 Hz, 2H), 0.03 (d, J = 4.0, 2 Hz). 340

2-chloro-6- ((1-(5-methyl- 2-((tetrahydro- 2H-pyran-4- yl)amino)-pyrimidin-4- yl)-1H- imidazole-4- carboxamido)- methyl)benzyl acetate1HNMR (400 MHz, DMSO-d₆) δ 8.63- 8.62 (t, J = 5.6 Hz, 1H), 8.34 (s, 1H),8.25 (s, 1H), 8.1 (s, 1H), 7.42-7.35 (m, 4H), 5.32 (s, 2H), 4.48 (d, J =6.4 Hz, 2H), 3.85-3.82 (m, 3H), 3.36 (t, J = 10.8 Hz, 1H), 2.17 (s, 3H),1.98 (s, 3H), 1.80 (d, J = 10.8 Hz,  3 2H), 1.49-1.47 (m, 2H). 341

N-(2-(3- chloro-2- (hydroxy- methyl)- phenyl) propan-2-yl)- 1-(5-methyl-2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- 1HNMR (400 MHz,DMSO-d₆): δ 8.33 (br s, 1H), 8.23 (br s, 1H), 7.98 (d, J = 11.6 Hz, 2H),7.42 (d, J = 7.6 Hz, 1H), 7.34-7.32 (m, 2H), 7.27-7.23 (m, 1H), 4.84 (s,3H), 3.84- 3.82 (m, 3H) 3.39- 3.33 (m, 2H), 2.16  3 yl)-1H- (s, 1H),1.80 (s, 7H), imidazole-4- 1.49-1.44 (m, 2H). carboxamide 342

(S)-2-chloro- 6-((1-(5- methyl-2- ((tetrahydro- furan-3- yl)amino)pyrimidin-4- yl)-1H- imidazole-4- carboxamido)- methyl)benzyl 1HNMR (400MHz, DMSO-d₆): δ 8.64- 8.61 (m, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.11(s, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.42-7.35 (m, 3H), 5.32 (s, 2H),4.55- 4.54 (m, 2H), 4.34 (br s, 1H), 3.87-3.78 (m, 2H), 3.72-3.66  3acetate (m, 1H), 3.55-3.51 (m, 1H), 2.18 (s, 3H), 2.15-2.10 (m, 1H),1.98 (s, 3H), 1.88-1.85 (m, 1H). 343

N-(4-chloro- 2-hydroxy- methyl- benzyl)-1-(5- methyl-2- ((tetrahydro-2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H- imidazole-4- carboxamide1HNMR (400 MHz, DMSO-d₆): δ 8.57 (t, J = 8.0 Hz, 1H), 8.34 (s, 1H), 8.25(s, 1H), 8.09 (s, 1H), 7.40 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.28 (d,J = 8.4 Hz, 2H), 5.33 (t, J = 5.2 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H),4.41 (d, J = 5.6 Hz, 2H),  3 3.89 (br s, 1H), 3.84 (d, J = 11.6 Hz, 2H),3.39-3.34 (m, 2H), 2.71 (s, 3H), 1.81 (d, J = 9.2 Hz, 2H), 1.52-1.44 (m,2H), 1.21 (s, 1H). 344

(R)-N-(3- chloro-2- (hydroxy- methyl)- benzyl)-1-(5- methyl-2-((tetrahydro- furan-3- yl)amino)- pyrimidin-4- yl)-1H- 1HNMR (400 MHz,DMSO-d₆): δ 8.63 (t, J = 6.4 Hz, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.12(s, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.33-7.23 (m, 3H), 5.24-5.22 (m, 1H),4.76 (d, J = 5.6 Hz, 2H), 4.61 (d, J = 6.4 Hz, 2H),  3 imidazole-4- 4.34(br s, 1H), carboxamide 3.87-3.78 (m, 2 H), 3.72-3.66 (m, 1H), 3.55-3.52(m, 1H), 2.19 (s, 3H), 2.15- 2.08 (m, 1H), 1.88- 1.84 (m, 1H) 345

((S)-N-(1-(3- chlorophenyl)- 2-((2-(methyl- amino)ethyl) amino)ethyl)-1-(5-methyl- 2-((tetrahydro- 2H-pyran-4- yl)amino)- pyrimidin-4- yl)-1H-imidazole-4- carboxamide 2,2,2- trifluoroacetate 1HNMR (400 MHz,DMSO-d₆): δ 8.93 (d, J = 8.0 Hz, 1H), 8.62 (br s, 1H), 8.56 (br s, 1H),8.36 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.54- 7.40 (m, 4H), 5.41 (s,1H), 3.90 (br s, 9H), 3.86-3.83 (m, 4H), 3.60-3.44 (m, 2H), 3.38-3.25(m, 6H), 2.61 (s, 3H), 2.16 (s, 3H), 1.80 (d, J = 11.2 Hz, 2H),1.50-1.49 (m, 2H) 20 346

(S)-2-chloro- 6-((1-(5- methyl-2- ((tetrahydro- furan-3- yl)amino)pyrimidin-4- yl)-1H- imidazole-4- carboxamido)- 1HNMR (400 MHz,DMSO-d₆): δ 8.64- 8.61 (m, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.11 (s,1H), 7.59 (d, J = 5.2 Hz, 1H), 7.41-7.35 (m, 3H), 5.33 (s, 2H), 4.54 (d,J = 6.4 Hz, 2H), 4.36 (br s, 1H) 3.87-  3 methyl)benzyl- 3.78 (m, 2H),3.72- propionate 3.66 (m, 1H), 3.55- 3.51 (m, 1H), 2.30- 2.24 (m, 2H),2.18 (s, 3H), 2.15-2.08 (m, 1H), 1.90-1.82 (m, 1H), 1.00-0.99 (m, 3H).347

(S)-N-(2-(3- chloro-2- (hydroxy- methyl)- phenyl)propan- 2-yl)-1-(5-methyl- 2-((tetrahydro- furan-3- yl)amino) pyrimidin-4- yl)-1H-imidazole-4- 1HNMR (400 MHz, DMSO-d₆): δ 8.35 (br s, 1H), 8.24 (br s,1H), 8.0 (d, J = 8.4 Hz, 2H), 7.58 (br s, 1H), 7.42 (d, J = 8.0 Hz, 1H),7.33 (d, J = 8.0 Hz, 1H), 7.27-7.23 (m, 1H), 4.83 (s, 3H), 4.33 (br s,1H), 3.86- 3.79 (m, 2H), 3.7- 3.67 (m, 1H), 3.53-  3 carboxamide 3.52(m, 1H), 2.17 (s, 3H), 2.17-2.11 (m, 1H), 1.9-1.85 (m, 1H), 1.80 (s,6H). 348

2-chloro-6- ((1-(5- methyl-2- ((tetrahydro- 2H-pyran-4- yl)amino)-pyrimidin-4- yl)-1H- imidazole-4- carboxamido)- methyl)benzyl-propionate 1HNMR (400 MHz, DMSO-d₆): δ 8.62 (t, J = 5.6 Hz, 1H), 8.34(s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.40-7.35 (m, 4H), 5.33 (s, 2H),4.54 (d, J = 6 Hz, 2H), 3.85-3.82 (m, 3H), 3.36 (t, J = 11.6 Hz, 2H),2.48-2.24 (m, 2H), 2.16 (s,  3 3H), 1.80 (d, J = 11.6 Hz, 2H), 1.52-1.44 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H).

Example 34. Biological Assays ERK1 and ERK2 HTRF (Biochemical) Assays

These assays employed a homogeneous time resolved fluorescence (HTRF)technique. The compounds were serially diluted by half-log withconcentrations ranging from 0.0005 to 10 uM in the assay buffer (50 mMTris pH=7.5, 1 mM EGTA, 2 mM DTT, 10 mM MgCl₂, 0.100 Tween-20) and 20 uLof substrate-ATP mix [1 uM Biotin-LC-Myelin Basic Protein (MBP)derivatized Peptide (Anaspec)-24 uM ATP (Sigma)] was added to each wellof the assay plate. Then 10 uL of enzyme mix [25 nM ERK1 or ERK2(Jubilant Biosys) in assay buffer] was added to each well. The plate wasincubated at room temperature for 60 min with shaking. The HTRF mix [625nM LANCER Ultra Europium-anti-phospho-MBP (Perkin Elmer) and 2 nMPhycolink® Streptavidin-Allophycocyanin (SA-APC) (Prozyme) in HTRFbuffer (50 mM Tris-HCl pH=7.5, 100 mM NaCl, 0.1% BSA, 0.05% Tween20, 0.5mM EDTA)] was prepared and 75 uL of this mix was added to the HTRFplate. After incubation for 60 min at room temperature, 10 uL of thereaction mixture was transferred to the HTRF assay plate and incubatedfor 45 min at room temperature with shaking. Plate was read usingPherastar in HTRF mode (excitation 337 nm, emission 665 & 620 nm). TheIC₅₀ values (half maximal inhibitory concentration values) weresubsequently determined using a sigmoidal dose-response curve (variableslope) in GraphPad Prism® 5 software. Compounds of the invention causedinhibition of ERK1 and ERK2 as determined in these assays.Representative data are provided in Table 2.

Cell Proliferation (Alamar Blue) Assay

HT-29 (colorectal carcinoma, B-RafV600E), HCT116 (colorectal carcinoma,K Ras G13D), A375 (melanoma, B-RafV600E) and SK-Mel2 (melanoma, NRASQ61R) cells (obtained from ATCC, USA) were seeded (5000 cells/well) in96-well tissue culture plate and incubated at 37° C./5% CO₂ for 16-24hours. The cells were then treated with compounds, at concentrationstypically from 0.0005 to 10 uM prepared in 3-fold serial dilutions. Theplates were then incubated for 72 h at 37° C./5% CO₂ in a moistenvironment. Then Alamar Blue™ reagent (final concentration 1×) wasadded to each well and incubated for 1-3 h at 37° C./5% CO₂. The plateswere read on fluorescence reader at 540 nm excitation and 590 nmemission wavelengths. The IC₅₀ values were subsequently determined usinga sigmoidal dose-response curve (variable slope) using GraphPad Prism® 5software. Compounds of the invention caused inhibition of HT-29, HCT116,A375 and SK-Mel2 cell proliferation as determined in these assays.Representative data for the HT-29 and HCT116 cell proliferation assaysare provided in Table 2.

Phospho-RSK1(S380) ELISA Assay

HT-29 cells (colorectal carcinoma, B-RafV600E); obtained from ATCC, USA)were seeded (60,000 cells/well) in a 96-well plate and incubated at 37°C./5% CO₂ overnight and then treated with desired compound dilutions for2 h. Medium was removed and cells were rinsed once with ice-cold 1×PBS,then 0.070 mL ice-cold 1× cell lysis buffer containing 1 mM PMSF wasadded to each well and the plate was incubated on a shaker for 2 h and30 min at 4° C. The plate was then centrifuged for 20 min (×4000 rpm) at4° C. and the supernatant was transferred to a new plate. Cell lysateswere diluted with sample diluent at a ratio of 1:1. The ELISA was thencarried out following the manufacturer's protocol (PathScan®phospho-RSK1(Ser380) Sandwich ELISA Kit, Cell Signaling Technologies).The plate was read at 450 nm within 30 min after adding STOP solution.The IC₅₀ values were subsequently determined using a sigmoidaldose-response curve (variable slope) in GraphPad Prism® 5 software.Compounds of the invention inhibited phosphorylation of RSK1(S380) (thedownstream target of ERK1/2) as determined in this assay. Representativedata are provided in Table 2.

In vivo Studies in Tumor Xenograft Models

Tumor Cell Implantation and Randomization of Animals

Foxn1 nu/nu strain of female mice (obtained from Charles RiverLaboratories, USA), 8-10 weeks of age, body weight range 23-25 g, wereused for the tumor xenograft efficacy studies. Human cancer cell lines(such as melanoma A375, colorectal HT29, pancreatic BxPC3, colorectalHCT116, and lung A549) were first grown in vitro, and then about fivemillion (5×10⁶) of these cells in 100 μL of serum free medium were mixedwith an equal amount of matrigel, and the entire mixture was injectedsubcutaneously at the right flank region of mice. The tumors weremeasured with Vernier calipers periodically after the first week ofinjection. When the tumor volume reached 120-150 mm³ (about 3-4 weeksafter injection) the animals were randomized into different groups sothat their tumor volume was approximately the same in all groups.

Determination of In Vivo Efficacy of Tumor Growth Inhibition

For PO dosing, the compounds were prepared in a formulation containing0.5% Methyl cellulose and 0.01% Tween 80. For IV, SC, or IP dosing, thecompounds were prepared in 6% solutol-ethanol (1:1), 6% DMSO and 88%saline. Animals were dosed with compounds prepared in specificformulations via PO, IP or SC route either QD or BID at the requireddoses. Tumors size and body weights were measured twice or thrice in aweek. Tumors were harvested at the end of the study after euthanizingthe animals according to approved protocols. From the harvested tumorone part was snap frozen and submitted for PK studies, and the otherpart was homogenized and the lysates were tested for target inhibitionusing western blotting. Before the tumor was harvested, blood (˜200 μL)was collected by ocular bleeding for PK studies.

Changes in tumor volume (Δ volumes) for each treated (T) and control (C)group were calculated by subtracting the mean tumor volume on the firstday of treatment (starting day) from the mean tumor volume on thespecified observation day. These values were used to calculate apercentage growth (% T/C) using the formula:

% T/C=(ΔT/ΔC)×100, where ΔT>0, or

% T/C=(ΔT/ΔTi)×100, where ΔT<0 and Ti is the mean tumor volume at thestart of the experiment.

Percentage tumor growth inhibition was calculated as [100−% T/C].Percentage body weight change was calculated as [(Body weight onspecified observation day−Body weight on starting day)/Body weight onstarting day]×100.

Results

Compounds of the invention were active in these in vivo tumor xenograftstudies. For example, in a human melanoma xenograft model (A375)harboring B-RAF V600E mutation, compounds of Example 201 and Example 211caused approximately 70 to 76% tumor growth inhibition when dosed orallyat 50 mg/kg BID for 17 days. There was no significant body weight lossobserved at this dose for either compound. In a pharmacodynamic assay,compounds of Example 201 and Example 211 caused inhibition ofphospho-RSK (the downstream target of ERK1/2) by about 66 and 84%,respectively, as measured in A375 tumor samples harvested at 1 h afterdosing at 50 mg/kg PO, when compared to the vehicle control. Also, inthis same model (A375), compounds of Example 255, Example 225a, andExample 259 caused approximately 70 to 90% tumor growth inhibition whendosed orally at 50 mg/kg BID for 19 days. There was no significant bodyweight loss observed at this dose for either compound.

In a human colon cancer xenograft model (HT-29) harboring B-RAF V600Emutation, the compound of Example 201 caused approximately 50% tumorgrowth inhibition when dosed orally at 50 mg/kg BID for 20 days. Therewas no significant body weight loss observed at this dose in this study.

In a human pancreatic carcinoma xenograft model, BxPC3 (wild type KRAS),the compound of Example 201 caused about 63% tumor growth inhibitionwhen dosed orally at 50 mg/kg BID for 25 days. There was no significantbody weight loss observed at this dose in this study.

In a human colon cancer xenograft model (HCT116; harboring KRASmutation), the compounds of Example 259, Example 225a, and Example 275caused approximately 90-100% tumor growth inhibition when dosed orallyat 50 mg/kg BID for 24 days. There was no significant body weight lossobserved at this dose in this study.

In a human lung carcinoma xenograft model (A549; harboring KRASmutation), the compound of Example 304, Example 302 and Example 300caused about 65 to 82% tumor growth inhibition when dosed orally at 50mg/kg BID for 20 days. There was no significant body weight lossobserved at this dose in this study.

TABLE 2 Biochemical, Mechanistic and Proliferation Cell-based AssayResults Biochemical Mechanistic Cell Proliferation Cmpd Assay¹ CellAssay² Assay² # ERK1 ERK2 RSK1 Phos HT29 HT29 HCT116 1 A A NA NA E 2 A BNA E E 3 B B NA E E 4 E E NA E E 5 C NA NA NA NA 6 A A E E E 7 B B NA EE 9 NA E NA NA NA 10 NA E NA NA NA 11 NA E NA NA NA 12 A A E E E 13 C CNA NA NA 14 C C NA NA E 15 B NA NA NA E 16 C B NA NA E 18 A C E E E 20 AA NA NA E 21 A A E E E 22 C B NA E E 23 A A E D E 24 A A E E E 25 A NANA NA NA 26 A NA NA NA NA 27 NA NA NA NA NA 28 B B NA NA NA 29 A A C C D30 A A NA E E 31 A A D C D 32 A A D E E 33 A A E NA E 34 A A E NA E 35 AA NA NA E 36 C A NA NA E 37 C A NA E D 38 A A E E E 39 B A NA E E 40 B BNA E E 41 C A NA E E 42 A A D C C 43 E E NA NA NA 44 B A NA E E 45 A ANA E E 46 A A NA E E 47 A A C B C 48 A A C C D 49 B A NA E E 50 NA A NAE E 51 C B NA E E 52 NA C NA NA NA 53 C C NA NA NA 54 B A NA E E 55 B BNA E E 56 NA C NA NA NA 57 A A NA E E 58 A A D D E 59 B A C C C 60 A A AA B 61 NA D NA NA NA 62 A A D D D 63 A A C D D 64 A A D C D 65 NA A A BB 66 A A B C D 67 A A D E E 68 A A A B B 69 A A D D D 70 A A C E D 71 AA C D E 72 A A A D E 73 A A E D D 74 A A D D E 75 A A D D E 76 A A C D E77 A A B D E 78 A A NA E E 79 C A NA E E 80 A A E E E 81 A A NA E E 82 BA NA E E 83 C A NA E E 84 A A NA E E 85 C C NA E E 86 B B NA E E 87 A AB C D 88 A A NA E E 89 C A NA E E 90 C A NA E E 91 A A D D E 92 A A NA DE 93 A A A A A 94 A A D NA D 95 B A C C D 96 A A C C D 97 NA C NA E E 98A A NA NA NA 99 C C NA E E 100 B A C E E 101 A A NA D E 103 C A NA E E104 NA C NA E E 105 A A B E E 106 A A B D E 107 A A D D D 108 A A NA E E109 A A C E E 110 B A E E E 111 B A NA E E 112 A A NA NA E 113 B A B B B114 A A B D C 115 A A C E E 116 A A D E E 117 C B D E E 118 B A C B D119 NA C NA E E 120 NA C NA E E 121 A A C C C 122 NA E NA NA NA 123 A AB C D 124 A A D D E 125 A A B C C 126 A A B B A 127 A A D E E 128 A A DD E 129 A A D E E 130 C C D E E 131 A A C C C 132 A A D D D 133 A A C CD 134 NA D NA NA NA 135 A A D NA NA 136 B A E D D 137 A A B C B 138 A AB B B 139 A A A C B 140 A A E D D 141 A A E E E 142 A A C D D 143 A A CD C 145 E D E NA NA 146 A A B D D 147 B A E E E 148 A A D D D 149 B A EE E 150 C A D E E 151 A A B A D 152 A A B B D 153 C C E E E 154 A A C DB 155 A A B C D 156 A A C C D 157 A A C C D 158 C B E D D 159 B A D D D160 A A D E E 161 A A A A C 162 A A A B D 163 A A B D E 164 A A D D E165 A A D E E 166 A A C D E 167 A A D D E 168 A B D E E 169 B B D C D170 A A E D E 171 A A E D E 172 A A B D C 173 A A B B B 174 A A E E E175 A A B A C 176 A A D D E 177 A A B A B 178 C C C E D 179 A A D D D180 A A C D E 181 A A D E E 182 A A D D C 183 B A D E E 184 A A D D C185 A A C C C 186 A A D D C 187 A A C C D 188 C C E E E 189 C D NA NA NA190 A B C E E 191 A B B C D 192 A A C C E 193 C C D E E 194 A A C C D195 A A B B D 196 A A D D D 197 A A C D E 198 A A D D D 199 A A D D E201 A A B A D 202 B B E D E 203 C C NA E E 204 B B D D E 205 A A B B C206 A A D D E 207 A A D C E 208 A A NA D E 209 A A NA E E 211 A A A A B212 A A D D E 213 A A C B C 214 A A E E E 215 B A D C E 216 A A D C D217 C C NA E E 218 C D NA E E 219 A A C B D 220 A A C B D 221 A A NA C D222 C B NA E E 223 A A NA C C 225 A A A A A  225a A A A A A  225b A A BA D 226 A A NA C E 227 A A NA B E 228 C C NA NA NA 229 A A NA A D 230 AA NA D E 231 A A NA NA NA 232 A A NA NA NA 233 A A A NA E 234 A A D NANA 235 A A B NA B 236 A A A A A 237 A A C NA E 238 A A C NA D 239 A A DNA E 240 A A B NA C 241 A A C NA E 242 A A C NA D 243 A A D NA E 245 A AC NA D 246 A A E NA E 247 A A A NA E 248 A A B NA A 249 D C D NA D 250 DC D NA E 251 A A A NA C 252 A A B NA C 253 A A D NA E 254 A A B NA A 255A A A A A 256 A A A NA A 257 A A C NA E 258 A A C NA D 259 A A B B A 260A A E NA E 261 A A D NA E 262 A A A NA D 264 A A A NA B 265 A A C NA B266 A A A NA A 267 A A B NA B 268 A A A NA A 269 A A A NA A 270 A A B AA 271 A A A NA A 272 A A C NA B 273 A A B NA A 274 A A B NA A 275 A A AA A 276 A A B C D 277 A A D C C 278 A A A NA A 279 A A B NA D 280 A A AA A 281 A A B D E 282 A A A A A 283 A A D D E 284 A A D C D 285 A A A AB 286 A A A A A 287 A A D A C 288 A A B A A 289 C B D NA E 290 A A A A A291 A A C C D 292 A A A NA A 293 A A D NA D 294 A A E NA NA 295 A A A NANA 296 A A D NA NA 297 A A C A B 298 A A NA NA NA 299 A A NA NA NA 300 AA NA NA NA 301 NA NA NA NA NA 302 A A NA NA NA 303 A A NA NA NA 304 A ANA NA NA 305 A A NA NA NA 306 A A B A A 307 A A D D NA 308 A A D E C 309A A D C D 310 C A E E E 311 B A D NA E 312 A A D NA E 313 A A C NA E 314A A C NA E 315 A A E E E 316 D C E E E 317 B A E E E 318 A A D D E 319 AA D E E 320 A A C C D 321 B A D E E 322 D D E E E 323 A A C E E 324 A AD E E 325 NA NA NA NA NA 326 A A A A A 327 A A B D E 328 A A C C E 329 AA A A C 330 A A C D E 331 A A A D D 332 A A A D C 333 A A A A A 334 A AA A A 335 A A B C E 336 A A A A B 337 A A B B D 338 A A D E D 339 A A AA A 340 A A A A A 341 A A C D D 342 A A B A A 343 A A B C C 344 A A NANA NA 345 A A E D D 346 B A NA NA NA 347 C B NA NA NA 348 A A NA NA NA¹Biochemical Assay: IC₅₀ values; A: ≤50 nM, B: >50 to 100 nM, C: >100 to500 nM, D: >500 nM to 2.5 uM, E: >2.5 uM, NA: Data not available²Mechanistic Cell Assay and Cell Proliferation Assays: IC₅₀ values; A:≤100 nM, B: >100-250 nM, C: >250-500 nM, D: >500 nM-2.5 uM, E: >2.5 uM;NA: Data not available.

In one embodiment, the compound selected from the group consisting of:

-   (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzo    furan-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;-   N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methyl-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)-amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;    and-   N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,    or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or    stereoisomer thereof.

In one embodiment, the compound of formula (I) defined in each of theprevious embodiments being a substantially pure stereoisomer.

In one embodiment, a composition comprising at least one compound offormula (I) defined in each of the previous embodiments or apharmaceutically acceptable salt, prodrug, solvate, hydrate, orstereoisomer thereof, and a pharmaceutically acceptable carrier.

In one embodiment, a composition comprising at least one compoundselected from the group consisting of:

-   (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;-   N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methyl-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)-amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;    and-   N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,    or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or    stereoisomer thereof, and a pharmaceutically acceptable carrier.

In one embodiment, a composition of each of above, further comprising anadditional therapeutic agent.

In one embodiment, a method of treating a condition treatable byinhibiting ERK1/2 comprising administration to an individual in need acomposition comprising a therapeutically effective amount of at leastone compound of formula (I) defined in each of the previous embodimentsas to at least slow the progression of the condition.

In one further embodiment, the condition is cancer of prostate, head,neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest,bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast,ovaries, vagina, testicles, skin, thyroid, blood, lymph nodes, kidney,liver, intestines, pancreas, brain, central nervous system, adrenalgland, skin or a leukemia or lymphoma.

-   In one embodiment, a method of treating a condition treatable by    inhibiting ERK1/2 comprising administration to an individual in need    a composition comprising a therapeutically effective amount of at    least one compound selected from the group consisting of:-   (S)-1-(2-(benzol[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;-   N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)-amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)-amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;-   N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;-   (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;    and-   N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,    or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or    stereoisomer thereof.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternative, modifications and variations are intendedto fall within the spirit and scope of the present invention.

1.-27. (canceled)
 28. A method of inhibiting ERK1/2, the methodcomprising contacting ERK1/2 with a compound that isN-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 29. Themethod of claim 28, wherein the contacting step is in vitro.
 30. Themethod of claim 28, wherein the contacting step is in vivo.
 31. Themethod of claim 28, wherein the compound is(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt thereof.
 32. The method of claim31, wherein the compound is(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:


33. The method of claim 31, wherein the compound is(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

mandelic acid salt.
 34. The method of claim 31, wherein the compound is(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-1amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

hydrochloric acid salt.
 35. The method of claim 31, wherein the compoundis(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

benzenesulfonic acid salt.
 36. A method of treating colorectal cancer,colon cancer, pancreatic cancer, thyroid cancer, lung cancer, ormelanoma, in a subject, the method comprising administrating a compoundthat isN-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 37. Themethod of claim 36, wherein the compound is(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methy-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

or a pharmaceutically acceptable salt thereof.
 38. The method of claim36, wherein the compound is(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide


39. The method of claim 36, wherein the compound is(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

mandelic acid salt.
 40. The compound of claim 36, wherein the compoundis(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

hydrochloric acid salt.
 41. The method of claim 36, wherein the compoundis(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)aminopyrimidin-4-yl)-1H-imidazole-4-carboxamide:

benzenesulfonic acid salt.
 42. A process for preparing a compound ofFormula I-C:

by contacting a compound of Formula [S]:

with a suitable reducing agent under suitable reaction conditions toprovide the compound of Formula I-C; wherein: R¹ is phenyl or 5- to10-membered heteroaryl, which is unsubstituted or substituted with 1-3substituents selected from halogen, C₁₋₆alkyl, CN, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₁₋₆alkyl,—C₁₋₆alkyl-N—(C₁₋₆alkyl)₂, —C₁₋₆alkyl-NH—C₁₋₆ alkyl-OH,—C₁₋₆alkyl-NH—C₁₋₆alkyl-C₃₋₁₀cycloalkyl,—C₁₋₆alkyl-NH—C₁₋₆alkyl-NH—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C(O)—C₁₋₆alkyl,—C₁₋₆alkyl-O—C(O)—C₁₋₆alkyl, —C₁₋₆alkyl-NH—C₀₋₆alkyl-(4- to 6-memberedheterocyclyl), or —C₁₋₆alkyl-NH—C₀₋₆alkyl-(5- to 6-membered heteroaryl),wherein the C₁₋₆alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, C₁₋₄alkyl, NH₂, hydroxyC₁₋₆alkyl, or aminoC₁₋₆alkyl R³ is H orC₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substituted with1-5 halogens; R⁴ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,—C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-(5- to 6-membered heteroaryl),C₁₋₆alkyl-(4- to 6-membered heterocyclyl), 4- to 10-memberedheterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein thealkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl isunsubstituted or substituted with 1-3 substituents selected fromhalogen, CN, —C(O)—NH₂, —C(O)—NH—C₁₋₆alkyl, —C(O)—N—(C₁₋₆ alkyl)₂,—O—C₁₋₆alkyl-NH₂, —O—C₁₋₆alkyl-NH—(C₁₋₆alkyl),—O—C₁₋₆alkyl-N(C₁₋₆alkyl)₂, 4- to 6-membered heterocyclyl, —C(O)-(4- to6-membered heterocyclyl), —O-phenyl, —O—C₁₋₆alkyl-(4- to 6-memberedheterocyclyl), C₁₋₆alkyl, C₂₋₆alknyl, hydroxyl, C₁₋₆alkoxyl, orhydroxyC₁₋₆alkyl, and the heterocyclyl or heteroaryl is unsubstituted orsubstituted with 1-3 substituents selected from halogen, C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, or 4- to 6-membered heterocyclyl; R⁵ is H, halogen,C₁₋₆alkyl, or OC₁₋₆alkyl, wherein C₁₋₆alkyl is unsubstituted orsubstituted with 1-5 halogens; R⁶ is H or C₁₋₆alkyl, wherein theC₁₋₆alkyl is unsubstituted or substituted with 1-5 halogens; R⁷ isC₁₋₆alkyl, wherein the C₁₋₆alkyl is unsubstituted or substituted with1-5 halogens; Y is CH, C—R⁷, or N; and n is 0 or
 1. 43. The process ofclaim 42, wherein the suitable reducing agent is Raney nickel inmethanolic ammonia.
 44. The process of claim 42, wherein the suitablereaction conditions are 25 psi hydrogen for 16 hours at about roomtemperature.